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7,601 | early data suggesting that essential oils might be a possible option for long term therapy of Malassezia skin infections, with additional studies needed. Treatment of Malassezia fungemia is complicated by the lack of standardized susceptibility testing references. Recent consensus recommendations name liposomal amphotericin B as first line treatment for systemic Malassezia infections, with amphoteri cin B deoxycholate as an alternative. Additionally, the involved catheter should be removed and any lipid infusion should be dis continued. Itraconazole, posaconazole, or voriconazole may be alternative agents, but fluconazole should be avoided, given that many patients with Malassezia bloodstream infections in existing clinical series were receiving fluconazole prophylaxis at the time of developing the infection. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 283 u Aspergillus 1929 The genus Aspergillus contains approximately 250 species, but most human disease is caused by Aspergillus fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans. Invasive disease is most commonly caused by A. fumigatus. Most cases of Aspergillus disease (aspergillosis) are caused by inhalation of airborne spores (conidia) that subsequently germinate into fungal hyphae and invade host tissue. When inhaled by an immunocom petent person, conidia are rarely deleterious, presumably because they are efficiently cleared by phagocytic cells. Macrophage and neutrophil mediated host defenses are required for resistance to invasive disease. Aspergillus is a relatively unusual pathogen in that it can create very different disease states depending on the host characteristics, includ ing allergic (hypersensitivity), saprophytic (noninvasive), chronic, or invasive disease. Immunodeficient hosts are at risk for invasive disease, whereas immunocompetent atopic hosts tend to develop allergic dis ease. Disease manifestations include primary allergic reactions; colo nization of the lungs or sinuses; localized infection of the lung or skin; chronic infection of the lung; invasive pulmonary disease; or widely disseminated disease of the lungs, brain, skin, eye, bone, heart, and other organs. Clinically, these syndromes often manifest with mild, nonspecific, and late onset symptoms, particularly in the immunosup pressed host, complicating accurate diagnosis and timely treatment. 283.1 Allergic Disease (Hypersensitivity Syndromes) William J. Steinbach ASTHMA Attacks of atopic asthma can be triggered by inhalation of Aspergillus conidia, producing allergic responses and subsequent bronchospasm. Exposure to fungi, especially Aspergillus, needs to be considered as a trigger in a patient with an asthma flare, especially in those patients with severe or recalcitrant asthma. ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease resulting from immunologic sensitization to Aspergillus antigens. It is primarily seen in patients with asthma or cystic fibrosis. Inhalation of conidia produces noninvasive colonization of the bronchial airways, resulting in persistent inflammation and development of hypersensi tivity inflammatory responses. Disease manifestations are the result of abnormal immunologic responses to A. fumigatus antigens and include wheezing, pulmonary infiltrates, bronchiectasis, and even fibrosis. There are eight primary diagnostic criteria for ABPA: episodic bronchial |
7,602 | obstruction, peripheral eosinophilia, immediate cutane ous reactivity to Aspergillus antigens, precipitating IgE antibodies to Aspergillus antigen, elevated total IgE, serum precipitin (specific IgG) antibodies to A. fumigatus, pulmonary infiltrates, and central bron chiectasis. Secondary diagnostic criteria include repeated detection of Aspergillus from sputum by identification of morphologically consis tent fungal elements or direct culture and coughing of brown plugs or specks. Radiologically, bronchial wall thickening, pulmonary infil trates, and central bronchiectasis can be seen. Treatment depends on relieving inflammation via an extended course of systemic corticosteroids. Addition of oral antifungal agents, such as itraconazole or voriconazole, is used to decrease the fungal burden and diminish the inciting stimulus for inflammation. Because disease activity is correlated with serum IgE levels, these levels are used as one marker to define duration of therapy. An area of research interest is the utility of anti IgE antibody therapy in the management of ABPA. ALLERGIC ASPERGILLUS SINUSITIS Allergic Aspergillus sinusitis is thought to be similar in etiology to ABPA. It has been primarily described in young adult patients with asthma and may or may not be seen in combination with ABPA. Patients often present with symptoms of chronic sinusitis or recur rent acute sinusitis, such as congestion, headaches, and rhinitis, and are found to have nasal polyps and opacification of multiple sinuses on imaging. Laboratory findings can include elevated IgE levels, pre cipitating antibodies to Aspergillus antigen, and immediate cutaneous reactivity to Aspergillus antigens. Sinus tissue specimens might contain eosinophils, Charcot Leyden crystals, and fungal elements consistent with Aspergillus species. Surgical drainage is an important aspect of treatment, often accompanied by courses of either systemic or inhaled steroids. Use of an antifungal agent may also be considered. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 283.2 Saprophytic (Noninvasive) Syndromes William J. Steinbach PULMONARY ASPERGILLOMA Aspergillomas are masses of fungal hyphae, cellular debris, and inflam matory cells that proliferate without vascular invasion, generally in the setting of preexisting cavitary lesions or ectatic bronchi. These cavitary lesions can occur as a result of infections such as tuberculosis, histo plasmosis, or resolved abscesses or secondary to congenital or acquired defects such as pulmonary cysts or bullous emphysema. Patients may be asymptomatic, with diagnosis made through imaging for other rea sons, or may present with hemoptysis, cough, or fever. On imaging, initially there may be thickening of the walls of a cavity, and later on there is a solid round mass separated from the cavity wall as the fungal ball develops. Detection of Aspergillus antibody in the serum suggests this diagnosis. Treatment is indicated for control of complications, such as hemoptysis. Surgical resection is the definitive treatment but has been associated with significant risks. Systemic antifungal treat ment with azole class agents is indicated in certain patients. CHRONIC PULMONARY ASPERGILLOSIS Chronic aspergillosis can occur in patients with normal immune sys tems or mild degrees of immunosuppression, including intermittent corticosteroids. Three major categories, each with overlapping clinical features, have been proposed to describe different manifestations of chronic aspergillosis. The first is |
7,603 | chronic cavitary pulmonary asper gillosis (CCPA), which is similar to aspergilloma, except that multiple cavities form and expand with occupying fungal balls. The second is chronic fibrosing pulmonary aspergillosis, where the multiple indi vidual lesions progress to significant pulmonary fibrosis. The final is subacute invasive aspergillosis (IA), which was previously called chronic necrotizing pulmonary aspergillosis, a slowly progressive pro cess found in patients with mild to moderate immune impairment. Treatment based on consensus guidelines can sometimes involve surgical resection, although long term antifungal therapy is often indi cated. Management of semi IA is similar to that of invasive pulmonary aspergillosis; however, the disease is more indolent, and thus there is a greater emphasis on oral therapy. Direct instillation of antifungals into the lesion cavity has been employed with some success. OTOMYCOSIS Aspergillus can colonize the external auditory canal, with possible extension to the middle ear and mastoid air spaces if the tympanic membrane is disrupted by concurrent bacterial infection. Symp toms include pain, itching, decreased unilateral hearing, or otorrhea. Chapter 283 Aspergillus William J. Steinbach Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1930 Part XV u Infectious Diseases Otomycosis is more often seen in patients with impaired mucosal immunity, such as patients with hypogammaglobulinemia, diabetes mellitus, chronic eczema, or HIV and those using chronic steroids. Treatments have not been well studied, but topical treatment with acetic or boric acid instillations or oral azoles such as voriconazole, itraconazole, and posaconazole have been described. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 283.3 Invasive Disease William J. Steinbach IA is primarily a disease of immunocompromised hosts, and common risk factors in adults include cancer or chemotherapy induced neutro penia, particularly if severe andor prolonged; hematopoietic stem cell transplantation, especially during the initial preengraftment phase or if complicated by graft versus host disease; neutrophil or macrophage dysfunction, as occurs in severe combined immunodeficiency (SCID) or chronic granulomatous disease (CGD); prolonged high dose steroid use; solid organ transplantation; and rarely, HIV. The most common site of primary infection is the lung, but primary invasive infection is also seen in the sinuses and skin and rarely elsewhere. Secondary infec tion can be seen after hematogenous spread, often to the skin, central nervous system (CNS), eye, bone, and heart. INVASIVE PULMONARY ASPERGILLOSIS Invasive pulmonary aspergillosis is the most common form of asper gillosis and plays a significant role in morbidity and mortality in the patient populations mentioned at increased risk for IA. Presenting symptoms can include fever despite initiation of empirical broad spectrum antibacterial therapy, cough, chest pain, hemoptysis, and pulmonary infiltrates. Patients on high dose steroids are less likely to present with fever. Symptoms in these immunocompromised patients can be very vague, and thus maintaining a high index of suspicion when confronted with a high risk patient is essential. Diagnosis Imaging can be helpful, although no finding is pathognomonic |
7,604 | for invasive pulmonary aspergillosis. Characteristically, multiple ill defined nodules can be seen, though lobar or diffuse consolidation is not uncommon, and normal chest x rays do not rule out disease. Classic radiologic signs on CT during neutropenia include the halo sign, when angioinvasion produces a hemorrhagic nodule surrounded by ischemia (Fig. 283.1). Early on there is a rim of ground glass opacification surrounding a nodule. Over time, these lesions evolve into cavitary lesions or lesions with an air crescent sign when the lung necroses around the fungal mass, often seen during recovery from neu tropenia. Unfortunately, these findings are not specific to invasive pul monary aspergillosis and can also be seen in other pulmonary fungal infections, and in pulmonary hemorrhage and organizing pneumonia. In addition, several reviews of imaging results of pediatric aspergillosis cases suggest that cavitation and air crescent formation are less com mon among these patients than among adult patients. On MRI, the typical finding for pulmonary disease is the target sign, a nodule with a lower central signal compared with the rim enhancing periphery. Conclusive diagnosis requires culture of Aspergillus from a normally sterile site and histologic identification of tissue invasion by fungal hyphae consistent with Aspergillus morphology. In addition, depend ing on the specimen type, a positive result from culture can represent colonization rather than infection; however, all positive cultures should be interpreted conservatively in high risk patients. Serology can be useful in the diagnosis of allergic Aspergillus syndromes and in asper gilloma but is low yield for invasive disease, likely because of deficient immune responses in the high risk immunocompromised popula tion. Bronchoalveolar lavage (BAL) can be useful, but negative culture results cannot be used to rule out disease, owing to inadequate sensitiv ity. Proven disease requires histologic confirmation or microbiologic recovery of the organism, whereas probable disease diagnosis includes radiographic findings coupled with molecular biologic assays such as galactomannan antigen detection either in the serum or from the BAL. This galactomannan assay has been shown to be the most sensitive in detecting disease in cancer patients or hematopoietic stem cell trans plant recipients, with less utility in solid organ transplant recipients. Earlier reports of increased false positive reactions in children versus adults have been refuted, and the galactomannan assay is effective in diagnosing IA in children. This test does possess high rates of false negativity in patients with congenital immunodeficiency (e.g., CGD) and invasive Aspergillus infections. The beta glucan assay is a nonspe cific molecular fungal assay that detects the major component of the fungal cell wall. Unlike the galactomannan assay, which is specific for Aspergillus, the beta glucan assay will not discriminate which fungal organism is infecting the patient. Polymerase chain reaction (PCR) based assays are in development for the diagnosis of aspergillosis but are still being optimized. Treatment Successful treatment of IA hinges on the ability to reconstitute normal immune function and use of effective antifungal agents until immune recovery can be achieved. Therefore lowering overall immunosuppres sion, specifically via cessation of |
7,605 | corticosteroid use, is vital to improve the ultimate outcome. Multiple published guidelines recommend that primary therapy for all forms of IA is voriconazole, based on several studies showing both improved response rates and improved survival in patients receiving voriconazole when compared with amphotericin B. Guideline recommended alternative therapies include liposomal amphotericin B, isavuconazole, and other lipid formulations of amphotericin B. European guidelines recommend isavuconazole and voriconazole for treatment of pulmonary disease with a similar strength of recommendation, mentioning fewer adverse effects with isavuconazole than with voriconazole and use of liposomal ampho tericin B as an alternative. Posaconazole is another triazole antifungal that is approved for antifungal prophylaxis and may be considered an alternative agent for first line treatment of IA. The echinocandin class of antifungals may also a play a role in treatment of IA, but to date, these agents are generally employed as second line medications, particularly for salvage therapy. Combination antifungal therapy has revealed disparate results. The U.S. guidelines state that combination primary antifungal therapy with voriconazole plus an echinocandin may be considered in select patients with doc umented IA; however, this is not a recommendation. Importantly, primary therapy with an echinocandin is not recommended, but an echinocandin can be used in the settings in which azole or polyene antifungals are contraindicated. Unfortunately, even with newer Fig. 283.1 Angioinvasive aspergillosis. CT section at the level of the lower trachea shows a consolidation with an eccentric cavitation and air crescent sign (arrows). This finding in this neutropenic patient is highly diagnostic of angioinvasive aspergillosis. (From Franquet T. Nonneo plastic parenchymal lung disease. In: Haaga JR, Boll DT, eds. CT and MRI of the Whole Body, 6th ed. Philadelphia: Elsevier; 2017: Fig. 36.14.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 284 u Histoplasmosis (Histoplasma capsulatum) 1931 antifungals, complete or partial response rates for treatment of IA are only approximately 50. To augment antifungal therapies, patients have been treated with growth factors to increase neutrophil counts, granulocyte transfusions, interferon , and surgery. Treatment of IA should be continued for a minimum of 6 12 weeks; however, many experts feel that treatment should continue until complete clinical and radiographic resolution of disease. Special Populations Patients with CGD represent a pediatric population at particular risk for pulmonary aspergillosis. Invasive pulmonary aspergillosis can be the first serious infection identified in these patients, and the lifetime risk of developing pulmonary aspergillosis is estimated to be 33. Unlike classical IA in cancer patients, the onset of symptoms is often gradual, with slow development of fever, fatigue, pneumonia, and ele vated sedimentation rate. The neutrophils of patients with CGD sur round the collections of fungal elements but cannot kill them, thereby permitting local invasion with extension of disease to the pleura, ribs, and vertebrae, though angioinvasion is not seen. Imaging in these patients is much less likely to reveal |
7,606 | the halo sign, infarcts, or cavitary lesions and instead generally shows areas of tissue destruction caused by the ongoing inflammatory processes. CUTANEOUS ASPERGILLOSIS Cutaneous aspergillosis can occur as a primary disease or as a con sequence of hematogenous dissemination or spread from underlying structures. Primary cutaneous disease classically occurs at sites of skin disruption, such as intravenous access device locations, adhesive dress ings, or sites of injury or surgery. Premature infants are at particular risk, given their immature skin and need for multiple access devices. Cutaneous disease in transplant recipients tends to reflect hematog enous distribution from a primary site of infection, often the lungs. Lesions are erythematous, indurated papules that progress to painful, ulcerated, necrotic lesions. Treatment depends on the combination of surgical debridement and antifungal therapy, with systemic voricon azole recommended as primary therapy. INVASIVE SINONASAL DISEASE Invasive Aspergillus sinusitis represents a difficult diagnosis because the clinical presentation tends to be highly variable. Patients can present with congestion, rhinorrhea, epistaxis, headache, facial pain or swell ing, orbital swelling, fever, or abnormal appearance of the nasal tur binates. Because noninvasive imaging can be normal, diagnosis rests on direct visualization via endoscopy and biopsy. Sinus mucosa may be pale, discolored, granulating, or necrotic, depending on the stage and extent of disease. The infection can invade adjacent structures, including the eye and brain. This syndrome is difficult to distinguish clinically from other types of invasive fungal disease of the sinuses such as mucormycosis, rendering obtaining specimens for culture and his tology extremely important. If the diagnosis is confirmed, treatment should be with voriconazole similar to invasive pulmonary disease. Because voriconazole is not active against mucormycosis, amphoteri cin B formulations should be considered in invasive fungal sinusitis pending definitive identification. CENTRAL NERVOUS SYSTEM The primary site of Aspergillus infection tends to be the lungs, but as the hyphae invade into the vasculature, fungal elements can dislodge and travel through the bloodstream, permitting establishment of secondary infection sites. One of the sites commonly involved in disseminated dis ease is the CNS. Cerebral aspergillosis can also arise secondary to local extension of sinus disease. The presentation of cerebral aspergillosis is highly variable but can include changes in mental status, seizures, paraly sis, coma, and ophthalmoplegia. As the hyphae invade the CNS vascu lature, hemorrhagic infarcts develop that convert to abscesses. Biopsy is required for definitive diagnosis, but patients are often too ill to toler ate surgery. Imaging can be helpful for diagnosis, and MRI is preferred. In general, the prognosis for CNS aspergillosis is extremely poor, likely owing to the late onset at presentation. Reversal of immunosuppression is extremely important, when possible. Surgical resection of lesions may be useful. Voriconazole is the best therapy, usually at high doses. EYE Fungal endophthalmitis and keratitis may be seen in patients with disseminated Aspergillus infection. Pain, photophobia, and decreased visual acuity may be present, though many patients are asymptomatic. Emergent ophthalmologic evaluation is important when these entities are suspected. Endophthalmitis is treated with intravitreal injection of either |
7,607 | amphotericin B or voriconazole along with surgical intervention and systemic antifungal therapy with voriconazole. Keratitis requires topical and systemic antifungal therapy. BONE Aspergillus osteomyelitis can occur, most commonly in the vertebrae. Rib involvement occurs as a result of extension of disease in patients with CGD and is most often caused by A. nidulans. Treatment depends on the combination of surgical debridement and systemic antifungals. Arthritis can develop after hematogenous dissemination or local exten sion, and treatment depends on joint drainage combined with antifun gal therapy. Voriconazole is the preferred first line therapy. HEART Cardiac infection can occur as a result of surgical contamination, secondary to disseminated infection, or after direct extension from a contiguous focus of infection and includes endocarditis, myocarditis, and pericarditis. Treatment requires surgical intervention in the case of endocarditis and pericarditis, along with systemic antifungals, some times lifelong because of the possibility of recurrent infection. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Histoplasmosis is caused by Histoplasma capsulatum, a dimorphic fun gus found in the environment as a saprobe in the mycelial (mold) form and in tissues in the parasitic form as yeast. EPIDEMIOLOGY Two varieties of Histoplasma cause human histoplasmosis. The most common variety, H. capsulatum var. capsulatum, is found in soil as the saprotrophic form throughout the midwestern United States, primarily along the Ohio and Mississippi rivers. In parts of Kentucky and Ten nessee, almost 90 of the population older than 20 years of age have positive skin test results for histoplasmin. Sporadic cases have also been reported in nonendemic states in patients without a travel his tory. Worldwide, H. capsulatum var. capsulatum is endemic to parts of Central and South America, the Caribbean, China, India, Southeast Asia, and the Mediterranean. The less common variety, H. capsulatum var. duboisii, is endemic to certain areas of western and central sub Saharan Africa. H. capsulatum thrives in soil rich in nitrates such as areas that are heavily contaminated with bird or bat droppings or decayed wood. Fungal spores are often carried on the wings of birds. Focal outbreaks of histoplasmosis have been reported after aerosolization of microconidia Chapter 284 Histoplasmosis (Histoplasma capsulatum) Matthew C. Washam and Lara A. Danziger Isakov Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1932 Part XV u Infectious Diseases Fig. 284.1 Radiograph of a 5 yr old child with acute pulmonary histo plasmosis showing right perihilar lymphadenopathy. resulting from construction in areas previously occupied by starling roosts or chicken coops or by chopping decayed wood or burning bamboo exposed to a blackbird roost. Unlike birds, bats are actively infected with Histoplasma. Focal outbreaks of histoplasmosis have also been reported after intense exposure to bat guano in caves and along bridges frequented by bats. Horizontal person to person transmission does not occur, although transplacental transmission of H. capsulatum has been reported in immunocompromised mothers. PATHOGENESIS Inhalation |
7,608 | of microconidia (fungal spores) is the initial stage of human infection. The conidia reach the alveoli, germinate, and pro liferate as yeast. Alternatively, spores can remain as mold with the potential for activation. Most infections are asymptomatic or self limited. When disseminated disease occurs, any organ system can be involved. The initial infection is a bronchopneumonia. As the initial pulmonary lesion ages, giant cells form, followed by formation of caseating or noncaseating granulomas and central necrosis. Granulo mas contain viable yeast, and disease can relapse. At the time of spore germination, yeast cells are phagocytosed by alveolar macrophages, where they replicate and gain access to the reticuloendothelial system via the pulmonary lymphatic system and hilar lymph nodes. Dissem ination with splenic involvement typically follows the primary pul monary infection. In normal hosts, specific cell mediated immunity follows in approximately 2 weeks, enabling sensitized T cells to acti vate macrophages and kill the organism. The initial pulmonary lesion resolves within 2 4 months but may undergo calcification resembling the Ghon complex of tuberculosis. Alternatively, buckshot calcifica tions involving the lung and spleen may be seen. Unlike tuberculosis, reinfection with H. capsulatum may occur and can lead to exagger ated host responses in some cases. Children with immune deficiencies, specifically deficiencies involv ing cell mediated immunity, are at increased risk for disseminated histoplasmosis. Primary immunodeficiencies involving pathogenic genetic variants in the interleukin (IL) 12interferon (IFN) path way have been reported in children with disseminated histoplasmo sis, including IL 12R1 deficiency and IFN R1 deficiency. Other primary immunodeficiencies identified in children with disseminated disease include STAT1 gain of function pathogenic genetic variants, idiopathic CD4 lymphopenia, AR DOCK8 deficiency, AD GATA2 deficiency, and X linked CD40L deficiency. Children with certain sec ondary immunodeficiencies (cancer patients, solid organ transplant recipients, children with HIV infection, and children receiving immu nomodulatory therapy with tumor necrosis factor TNF inhibitors) are also at increased risk for disseminated disease. CLINICAL MANIFESTATIONS Exposure to Histoplasma is common in endemic areas, although most infections are subclinical. Less than 1 of those infected display the following clinical manifestations: Acute pulmonary histoplasmosis follows initial or recurrent respi ratory exposure to microconidia. Symptomatic disease occurs more often in young children; in older patients, symptoms follow expo sure to large inocula in closed spaces (e.g., chicken coops or caves) or prolonged exposure (e.g., camping on contaminated soil, chopping decayed wood). The median incubation time is 14 days. The prodrome is not specific and usually consists of flulike symptoms, including headache, fever, chest pain, cough, and myalgias. Hepatosplenomeg aly occurs more often in infants and young children. Symptomatic infections may be associated with significant respiratory distress and hypoxia and can require intubation, mechanical ventilation, and ste roid therapy. Acute pulmonary disease can also manifest with a pro longed illness (10 days to 3 weeks) consisting of weight loss, dyspnea, high fever, asthenia, and fatigue. Children with symptomatic disease typically have a patchy bronchopneumonia; hilar lymphadenopathy is variably present (Fig. 284.1). In young children, the pneumonia can coalesce. |
7,609 | Focal or buckshot calcifications are convalescent findings in patients after acute pulmonary infection. Complications of pulmonary histoplasmosis occur secondary to exaggerated host responses to fungal antigens within the lung paren chyma or hilar lymph nodes. Histoplasmomas are of parenchymal ori gin and are usually asymptomatic. These fibroma like lesions are often concentrically calcified and single. Rarely, these lesions produce bron cholithiasis associated with stone spitting, wheezing, and hemopty sis. In endemic regions, these lesions can mimic parenchymal tumors and are occasionally diagnosed at lung biopsy. Mediastinal granulo mas form when reactive hilar lymph nodes coalesce and mat together. Although these lesions are usually asymptomatic, huge granulomas can compress the mediastinal structures, producing symptoms of esopha geal, bronchial, or vena caval obstruction. Local extension and necrosis can produce pericarditis or pleural effusions. Mediastinal fibrosis is a rare complication of mediastinal granulomas and represents an uncon trolled fibrotic reaction arising from the hilar nodes. Structures within the mediastinum become encased within a fibrotic mass, producing obstructive symptomatology. Superior vena cava syndrome, pulmo nary venous obstruction with a mitral stenosislike syndrome, and pulmonary artery obstruction with congestive heart failure have been described. Dysphagia accompanies esophageal entrapment, and a syn drome of cough, wheeze, hemoptysis, and dyspnea accompanies bron chial obstruction. Rarely, children develop a sarcoid like disease with arthritis or arthralgia, erythema nodosum, keratoconjunctivitis, irido cyclitis, and pericarditis. Pericarditis, with effusions both pericardial and pleural, is a self limited benign condition that develops as a result of an inflammatory reaction to adjacent mediastinal disease. The effu sions are exudative, and the organism is rarely culturable from fluid. Progressive disseminated histoplasmosis can occur in infants and in children with deficient cell mediated immunity. Disseminated disease may occur either during the initial acute infection in children with pri mary or secondary immunodeficiencies affecting T cell function (see Pathogenesis), in infants, or as a reactivation of a latent focus of infec tion within the reticuloendothelial system in children who acquire an immunosuppressive condition years after primary infection. Dissemi nated histoplasmosis in an HIV infected patient is an AIDS defining illness. Fever is the most common finding and can persist for weeks to months before the condition is diagnosed. The majority of patients have hepatosplenomegaly, lymphadenopathy, and interstitial pul monary disease. Extrapulmonary infection is a characteristic of dis seminated disease and can include destructive bony lesions, Addison Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 284 u Histoplasmosis (Histoplasma capsulatum) 1933 disease, meningitis, multifocal chorioretinitis, and endocarditis. Some patients develop mucous membrane ulcerations and skin findings such as nodules, ulcers, or molluscum like papules. A sepsis like syndrome has been identified in a small number of HIV infected patients with disseminated histoplasmosis and is characterized by the rapid onset of shock, multiorgan failure, and coagulopathy. Reactive hemophagocytic syndrome has been described in immunocompromised patients with severe disseminated histoplasmosis. Many children |
7,610 | with disseminated disease experience transient hyperglobulinemia. Elevated acute phase reactants and hypercalcemia are typically seen but are nonspecific. Anemia, thrombocytopenia, and pancytopenia are variably pres ent; elevated liver function tests and high serum concentrations of angiotensin converting enzyme may be observed. Chest radiographs are normal in more than half of children with disseminated disease. Chronic pulmonary histoplasmosis is an opportunistic infection in adult patients with centrilobular emphysema. Chronic progressive disseminated histoplasmosis is a slowly progressive infection caused by Histoplasma that occurs in older adults without obvious immuno suppression that is uniformly fatal if untreated. These entities are rare in children. DIAGNOSIS Optimal diagnosis of suspected histoplasmosis depends on the clini cal presentation and underlying immune status of the patient. Using serum and urine antigen tests along with serum antibody tests via com plement fixation and immunodiffusion yields a diagnostic sensitivity 90 for acute pulmonary and disseminated forms of histoplasmosis. Diagnostic testing options include the following: Antigen detection is the most widely available diagnostic study for patients with suspected pulmonary histoplasmosis or progressive disseminated histoplasmosis. Current laboratory methodology uses enzyme immunoassay (EIA) to detect H. capsulatum polysaccharide antigen in urine, blood, bronchoalveolar lavage fluid, and cerebrospinal fluid. In patients at risk for disseminated disease, antigen can be dem onstrated in the urine, blood, or bronchoalveolar lavage fluid in more than 90 of cases. Antigenuria has been shown to correlate with sever ity of disseminated histoplasmosis. Serum, urine, and bronchoalveolar lavage fluid from patients with acute or chronic pulmonary infections are variably antigen positive. In one study, antigenuria was present in 83 of patients with acute pulmonary disease and 30 of patients with subacute pulmonary disease. False positive results on urinary antigen testing can occur in patients with Blastomyces dermatitidis, Coccidioi des immitis, Coccidioides posadasii, Paracoccidioides brasiliensis, and Penicillium marneffei. Testing both urine and serum samples for histo plasma antigen increases the sensitivity compared with testing only the urine or serum alone. Sequential measurement of serum antigen levels in patients with disseminated disease is useful for monitoring response to therapy; persistent low level antigenuria may occur in some patients who have completed therapy and have no evidence of active infection. Antibody tests continue to be useful for the diagnosis of acute pul monary histoplasmosis, its complications, and chronic pulmonary disease. Serum antibody to yeast and mycelium associated antigens is classically measured by complement fixation. Although titers of 1:8 are found in more than 80 of patients with histoplasmosis, titers of 1:32 are most significant for the diagnosis of recent infection. Complement fixation antibody titers are often not significant early in the infection and do not become positive until 4 6 weeks after exposure. A fourfold increase in either yeast or mycelial phase titers or a single titer of 1:32 is presumptive evidence of active infection. Complement fixation titers may be falsely positive in patients with other systemic mycoses such as B. dermatitidis and C. immitis and may be falsely negative in immu nocompromised patients. Antibody detection by immunodiffusion is less sensitive but |
7,611 | more specific than complement fixation and is used to confirm questionably positive complement fixation titers. An EIA based method that has improved sensitivity and specificity compared with other serologic methods has been developed. The highest sensitiv ity for antibody testing can be achieved by combining methodologies. Culture sensitivity of tissue or body fluid samples is generally high est for children with progressive disseminated histoplasmosis or acute pulmonary histoplasmosis caused by a large inoculum of organisms. Histoplasma typically grows within 6 weeks on Sabouraud agar at 25C (77F). Identification of tuberculate macroconidia allows for only a presumptive diagnosis, because Sepedonium species form similar structures. A confirmatory test using a chemiluminescent DNA probe for H. capsulatum is necessary to establish a definitive identification. The yeast can be recovered from blood or bone marrow in 90 of patients with progressive disseminated histoplasmosis. Sputum cul tures are rarely obtained and are variably positive in normal hosts with acute pulmonary histoplasmosis; cultures of bronchoalveolar lavage fluid appear to have a slightly higher yield than sputum cultures. Blood cultures are sterile in patients with acute pulmonary histoplasmosis, and cultures from any source are typically sterile in patients with the sarcoid form of the disease. Histologic examination can identify yeast forms in tissue from patients with complicated forms of acute pulmonary disease (histo plasmoma and mediastinal granuloma). Tissue should be stained with methenamine silver or periodic acidSchiff stains, and yeast can be found within or outside of macrophages. In children with disseminated disease, organisms can be identified from bone marrow, liver, and mucocutaneous lesions. In those who are severely ill, Wright stain of peripheral blood can demonstrate fungal elements within leukocytes. Examination of fibrotic tissue from children with mediastinal fibrosis usually demonstrates no organisms. Real time polymerase chain reaction has been used on formalin fixed, paraffin embedded biopsy tissue and has an analytical sensitivity of at least 6 pgL from tissue extracted DNA and a clinical sensitivity and specificity of 88.9 and 100, respectively. Although not widely available, molecular methods may ultimately provide a more timely and accurate diagnosis. Skin testing is useful only for epidemiologic studies, as cutaneous reactivity is lifelong and intradermal injection can elicit an immune response in otherwise seronegative persons. Reagents are no longer commercially available. TREATMENT Acute pulmonary histoplasmosis does not require antifungal therapy for asymptomatic or mildly symptomatic children. Oral itraconazole (4 10 mgkgday in two divided doses, not to exceed 400 mg daily) for 6 12 weeks should be considered in patients with acute pulmonary infections who fail to improve clinically within 1 month. Although it appears to be less effective, fluconazole may be considered as an alter native therapy in children intolerant to itraconazole. Clinical experi ence in treating histoplasmosis with the newer azoles (voriconazole and posaconazole) is increasing, with posaconazole having increased in vitro activity. Patients with pulmonary histoplasmosis who become hypoxemic or require ventilatory support should receive amphotericin B deoxycholate (0.7 1.0 mgkgday) or amphotericin B lipid com plex (3 5 mgkgday) until improved, and adjunctive corticosteroids |
7,612 | (intravenous methylprednisolone at a dose of 0.5 1 mgkgday) can be considered for 1 2 weeks; continued therapy with oral itraconazole for a minimum of 12 wk is also recommended. The lipid preparations of amphotericin are not preferentially recommended in children with pulmonary histoplasmosis, as the classic preparation is generally well tolerated in this patient population. Patients with severe obstruc tive symptoms caused by granulomatous mediastinal disease may be treated sequentially with amphotericin B followed by itraconazole for 6 12 months, and inclusion of adjunctive corticosteroids should be considered for the first 1 2 weeks. Patients with milder mediastinal disease may be treated with oral itraconazole alone. Some experts rec ommend that surgery be reserved for patients who fail to improve after 1 month of intensive amphotericin B therapy. Sarcoid like disease with or without pericarditis may be treated with nonsteroidal antiinflamma tory agents for 2 12 weeks. Progressive disseminated histoplasmosis usually requires ampho tericin B deoxycholate (1.0 mgkgday for 4 6 weeks) or amphoteri cin B lipid complex (3 5 mgkgday). Alternatively, amphotericin B may be given for 2 4 weeks followed by oral itraconazole (4 10 mg kgday in two divided doses) as maintenance therapy for 12 months, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1934 Part XV u Infectious Diseases depending on Histoplasma antigen status. Longer therapy may be needed in patients with severe disease, immunosuppression, or pri mary immunodeficiency syndromes. It is recommended to monitor blood levels of itraconazole during treatment, aiming for a concentra tion of 1 gmL but 10 gmL to avoid potential drug toxicity. It is also recommended to monitor urine antigen levels during therapy and for 12 months after therapy has ended to ensure cure. Relapses in immunocompromised patients with progressive disseminated his toplasmosis are relatively common. Lifelong suppressive therapy with daily itraconazole (5 mgkgday up to adult dose of 200 mgday) may be required if immunosuppression cannot be reversed. For severely immunocompromised HIV infected children living in endemic regions, itraconazole (2 5 mgkg every 12 24 hours) may be used pro phylactically. Care must be taken to avoid interactions between anti fungal azoles and protease inhibitors. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY The etiologic agents of blastomycosis belong to a species complex and include Blastomyces dermatitidis, B. gilchristii, B. helicus, B. emzantsi, B. percursus, B. parvus, and B. silverae. The latter two species (B. parvus, B. silverae) rarely cause human infection. All Blastomyces species exhibit thermal dimorphism in which they grow as mold and produce spores in the soil at environmental temperature (2225C 71.677F) and as pathogenic yeast at core human body temperature (37C 98.6F). Once in tissue, Blastomyces infection results in pyogranulomatous inflammation, which is characterized by neutrophil infiltration and granuloma formation. Blastomyces yeast can be differentiated from other fungi by the presence of a broad based budding pattern between dividing |
7,613 | yeast cells, which occurs in all Blastomyces species. EPIDEMIOLOGY Blastomyces species cause disease in immunocompetent and immuno compromised children. Approximately 213 of blastomycosis cases occur in the pediatric population (average age: 9.1 12.9 years; range: 19 days to 18 years). Blastomycosis of newborns and infants is rare. In North America, the traditional geographic range of blastomyco sis cases is restricted to the Midwest, southcentral, and southeastern United States and parts of Canada bordering the Great Lakes and Saint Lawrence River Valley. In these geographic regions, several areas are hyperendemic for blastomycosis (e.g., Marathon and Vilas counties, Wisconsin; central and southcentral Mississippi; Kenora, Ontario). Outside of North America, autochthonous infections have been reported from Africa (100 cases), India (12 cases), and Israel. B. der matitidis is not endemic to Central America, South America, Europe, Asia, or Australia. In North America, B. dermatitidis and B. gilchristii grow in an eco logic niche characterized by forested, sandy soils with an acidic pH that have decaying vegetation and are near water. B. dermatitidis is located throughout the traditional geographic range, whereas B. gil christii is restricted to Minnesota, Wisconsin, Canada, and areas along the St. Lawrence River. B. helicus is located in the western United States (California, Montana, Idaho, Colorado, Nebraska, Texas) and Canada (Saskatchewan, Alberta); however, its environmental niche remains Chapter 285 Blastomycosis Gregory M. Gauthier and Bruce S. Klein to be determined. In Africa, there are multiple species of Blastomyces, including B. dermatitidis, B. gilchristii, B. percursus, and B. emzantsi. Knowledge about the ecological niche and geographic distribution of Blastomyces species in Africa is limited. B. percursus has been reported from Israel. Most Blastomyces infections are sporadic, but at least 20 outbreaks have been reported, and most of these outbreaks have included pedi atric patients. Outbreaks have been associated with construction or outdoor activities (camping, hiking, fishing, rafting on a river, using a community compost pile); however, some outbreaks have no identifi able risk factors other than geography. Although blastomycosis is often thought to be an infection that primarily affects persons residing in or visiting rural areas, outbreaks and sporadic cases of blastomycosis are well reported in urban areas. Blastomycosis outbreak investigations in Wisconsin suggested that persons of Hmong ethnicity are at increased risk for the disease, which may be the result of polymorphisms in the interleukin 6 (IL 6) gene. These polymorphisms result in reduced IL 6 cytokine production and CD4 T lymphocytes that produce IL 17, which in turn, impairs activation of neutrophils and macrophages against Blastomyces. Although persons of Hmong ethnicity are at increased risk for blastomycosis, they do not appear to be at risk for disseminated infection. Increased incidence of blastomycosis has also been reported in indigenous persons living in the United States and Canada. The severity of infection is influenced by the size of the inhaled inoculum and the integrity of the patients immune system. Solid organ transplant recipients are at risk for severe pulmonary blastomycosis, including acute respiratory distress syndrome (ARDS); however, they are not at |
7,614 | higher risk for disseminated infection. Although blastomy cosis is uncommon in persons immunosuppressed with AIDS, there is an increased risk for dissemination to the central nervous system (CNS). Persons receiving tumor necrosis factor inhibitors are at risk for blastomycosis, but rates of dissemination or severe disease are not well defined. PATHOGENESIS The ability of mycelial fragments and spores to convert to yeast in the lung is a crucial event in the pathogenesis of infection with Blastomyces and other dimorphic fungi. This temperature dependent morphologic shift, which is known as the phase transition, enables Blastomyces to evade the host immune system and establish infection. In the yeast form, the essential virulence factor BAD1 (Blastomyces adhesin 1; for merly WI 1) is secreted into the extracellular milieu and binds back to chitin on the fungal cell wall. BAD1 is a multifunctional protein that promotes binding of yeast to alveolar macrophages (via CR3 and CD14 receptors) and lung tissue (via heparan sulfate), blocks the depo sition of complement on the yeast surface, binds calcium, suppresses the hosts ability to produce cytokines (tumor necrosis factor , IL 17, interferon gamma), and inhibits activation of CD4 T lymphocytes. Deletion of BAD1 abolishes virulence of Blastomyces yeast in a murine model of pulmonary infection. The phase transition between mold and yeast forms is a complex event that involves alteration in cell wall composition, metabolism, intracellular signaling, and gene expression. The morphologic shift to yeast is regulated in part by a histidine kinase known as DRK1 (dimorphism regulating kinase 1). This sensor kinase controls not only the conversion of mold to yeast but also spore production, cell wall composition, and BAD1 expression; the loss of DRK1 gene expression through gene disruption renders B. dermatitidis aviru lent in a murine model of pulmonary blastomycosis. The function of DRK1 is conserved in other thermally dimorphic fungi, including Histoplasma capsulatum and Talaromyces marneffei (formerly Penicil lium marneffei). The phase transition is reversible, and after a drop in temperature from 37C (98.6F) to 22C (71.6F), yeast convert to sporulating mold. Growth as mold promotes survival in the soil, allows for sexual reproduction to enhance genetic diversity, and facilitates transmission to new hosts (via spores and mycelial fragments). The transition from Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 285 u Blastomycosis 1935 yeast to mold is influenced by SREB (siderophore biosynthesis repres sor in Blastomyces) and N acetylglucosamine transporters (NGT1, NGT2). Deletion of SREB, which encodes a GATA transcription fac tor, results in the failure of B. dermatitidis yeast to complete the con version to mold at 22C. N Acetylglucosamine, which polymerizes to form chitin, accelerates the transition to hyphae via NGT1 and NGT2 transporters. Innate and adaptive immune systems are required to effectively con trol infection; humoral immunity is dispensable. Macrophages and neutrophils are capable of ingesting and killing Blastomyces conidia. In contrast, |
7,615 | yeast are poorly killed by nonactivated macrophages, are resistant to reactive oxygen species, and suppress nitric oxide pro duction. Adaptive immunity is mediated by T lymphocytes (Th1 and Th17), which activate macrophages and neutrophils to facilitate clear ance of infection. After infection, cell mediated immunity against Blas tomyces can last for at least 2 years. CLINICAL MANIFESTATIONS The clinical manifestations of blastomycosis are diverse and include subclinical infection, symptomatic pneumonia, and disseminated dis ease. Clinical disease develops 3 weeks to 3 months after inhalation of spores or mycelial fragments. Asymptomatic or subclinical infections are estimated to occur in 50 of patients. The most common clinical manifestation of blastomycosis is pneu monia, which can range from acute to chronic. Acute symptoms resemble community acquired pneumonia and include fever, dys pnea, cough, chest pain, and malaise (Fig. 285.1). Respiratory failure, including ARDS, can occur in patients with an overwhelming burden of infection. The most common chest imaging pattern is air space con solidation with or without air bronchograms. Any lobe of the lung can be involved, and multiple lobe involvement is not uncommon. Other radiographic features include masslike consolidation, nodules with cavity formation, reticulonodular pattern, and miliary disease. Hilar adenopathy and pleural effusions occur in approximately 20 of cases. Because the clinical and radiographic features often mimic bacterial pneumonia, patients can be mistakenly treated with antibiotics, result ing in disease progression, which can result in disseminated disease or respiratory failure, including ARDS. Patients with subacute or chronic pneumonia experience fevers, chills, night sweats, cough, weight loss, hemoptysis, dyspnea, and chest pain. Mass lesions and cavitary disease on chest roentgenography can mimic malignancy and tuberculosis, respectively. Extrapulmonary blastomycosis most often affects the skin or bone but can involve almost any organ. The incidence of extrapul monary blastomycosis in children ranges from 38 to 50, similar to rates in adult patients (1548). B. dermatitidis is more likely to cause disseminated infection, whereas B. gilchristii is more likely to remain localized to the lungs. The skin is the most common site for extrapulmonary blastomycosis, which is usually the result of hema togenous dissemination. Direct inoculation of B. dermatitidis into the skin from trauma or a laboratory accident can result in primary cuta neous blastomycosis. Skin manifestations include plaques, papules, ulcers, nodules, and verrucous lesions. Erythema nodosum is rare in blastomycosis. Dissemination of B. dermatitidis to the bone results in lytic destruction, pain, soft tissue swelling, sinus tract formation, and ulceration. The ribs, skull, spine, and long bones are most commonly affected. Patients with osteomyelitis often have pulmonary or cutane ous involvement. Vertebral osteomyelitis can be complicated by para spinal abscess, psoas abscess, and vertebral body collapse. Extension of long bone osteomyelitis can result in pathologic fracture or septic arthritis. Genitourinary blastomycosis occurs in just under 10 of adults but is rare in children. CNS blastomycosis (brain abscess, meningitis) occurs in 10 of immunocompetent patients but in up to 40 of persons with AIDS. The majority of patients with CNS blastomycosis have clinically appar ent infection |
7,616 | at non CNS sites (e.g., lung, skin, mass lesion). Symptoms of CNS infection include headache, altered mental status, memory loss, seizure, cranial nerve deficits, and focal neurologic deficits. Compli cations include hydrocephalus, cerebral herniation, infarction, pan hypopituitarism, residual weakness, and poor functioning in school. Lumbar puncture demonstrates leukocytosis with a neutrophil or lym phocyte predominance, elevated protein, and low glucose. Growth of Blastomyces in culture from cerebrospinal fluid occurs in less than 50 of affected patients. Blastomycosis can complicate pregnancy, and clinical informa tion is limited to case reports. Disseminated infection involving the lungs, skin, and bone is common. Spread of infection to the placenta has been documented by histopathology; however, the frequency of placental blastomycosis remains unknown. Transmis sion of Blastomyces to the fetus is uncommon and is postulated to occur through transplacental transmission or aspiration of infected vaginal secretions. Although clinical data are limited, blastomycosis during pregnancy does not appear to increase the risk for congeni tal malformations. DIAGNOSIS The diagnosis of blastomycosis requires a high index of suspicion because the clinical and radiographic manifestations can mimic other diseases, including community acquired pneumonia, tuberculosis, and malignancy. The misdiagnosis of blastomycosis, most often as community acquired pneumonia, results in a delay of therapy and progression of disease, including dissemination and respiratory fail ure. In addition, absence of exposure to traditional environmental risk factors for blastomycosis can lead to a delay in diagnosis. Blasto mycosis should be included in the differential diagnosis for patients with pneumonia who (1) live in or visit areas in which this pathogen is endemic, (2) fail to respond to a treatment course of antibiotics, or (3) have concomitant skin lesions or osteomyelitis. A detailed medical his tory regarding exposure risks (e.g., canoeing, rafting, hiking, fishing, playing in outdoor forts, beaver dam exploration, home remodeling, nearby road or building construction, woodpile for a wood burning stove, and use of a community compost pile) should be obtained. In addition, the health of family pets such as dogs should be ascertained, as canine disease may be a harbinger of human infection. Studies from Wisconsin and Minnesota have demonstrated that 7.710 of persons with blastomycosis have a dog with concomitant or prior blastomy cosis. The incidence of canine blastomycosis is 10 fold higher than human blastomycosis, and canine infection suggests a common source of environmental Blastomyces exposure. Growth of Blastomyces in culture from sputum, skin, bone, or other clinical specimens provides a definitive diagnosis. Sputum specimens should be stained with 10 potassium hydroxide or calcofluor white. Histopathology shows neutrophilic infiltration with noncaseating Fig. 285.1 Left lung infection in a patient with symptoms resembling acute bacterial pneumonia. Organisms of Blastomyces in the sputum seen with potassium hydroxide preparation, and subsequent culture confirmed the diagnosis. (From Bradsher RW Jr. Blastomycoses. In: Bennett JE, Blaser MJ, Dolin R, et al, eds. Mandell, Douglas, and Ben netts Principles and Practice of Infectious Diseases, 8th ed, Philadel phia: Saunders; 2015: Fig. 266 5.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from |
7,617 | ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1936 Part XV u Infectious Diseases granulomas (pyogranulomas). Blastomyces yeast in tissue samples can be visualized using Gomori methenamine silver or periodic acid Schiff stains. Yeasts are 4 29 m in size, have a double refractile cell wall, and are characterized by broad based budding between mother and daughter cells. Nonculture diagnostic techniques should be used in conjunc tion with fungal smears and cultures to facilitate the diagnosis of blastomycosis. The development of a Blastomyces antigen test has supplanted insensitive serologic methods such as complement fixation and immunodiffusion. Urine, serum, cerebrospinal fluid, and bronchoalveolar fluid specimens can be collected for the Blas tomyces antigen test. Sensitivity of the urine antigen test ranges from 85 to 93 and is influenced by the burden of infection. The antigen test has similar sensitivity for B. dermatitidis and B. gilchristii, but ability to detect other species is poorly character ized. The antigen test can cross react with other dimorphic fungi, including Histoplasma capsulatum, Paracoccidioides brasiliensis, and Penicillium marneffei, decreasing the specificity to 76.979. An antibody test against the BAD1 protein has been developed and has a sensitivity of 87.8 and a specificity of 9499; however, this test is not yet commercially available. Combination antigen and BAD1 antibody testing can increase diagnostic sensitivity to 97.6. TREATMENT Antifungal therapy is influenced by the severity of the infection, involvement of the CNS, the integrity of the hosts immune system, and pregnancy. All persons diagnosed with blastomycosis should receive antifungal therapy. Newborns with blastomycosis should be treated with amphotericin B deoxycholate 1 mgkgday. Children with mild to moderately severe infection can be treated with itraconazole 10 mgkgday (maximum: 400 mgday) for 6 12 months. Children with severe disease, immunodeficiency, or immunosuppression should be treated with amphotericin B deoxycholate 0.7 1.0 mgkgday or lipid amphotericin B 3 5 mgkgday until there is clinical improve ment, generally 7 14 days, and then itraconazole 10 mgkgday (maxi mum: 400 mgday) for a total of 12 months. Central nervous system blastomycosis requires therapy with lipid amphotericin B 5 mgkgday for 4 6 weeks, followed by itraconazole, fluconazole, or voriconazole for 12 months. All pediatric patients of childbearing age should undergo pregnancy testing before initiation of azole antifungals. Itraconazole can increase the risk for spontaneous abortion, and fluconazole can cause cranio facial defects resembling Antley Bixler syndrome. Voriconazole and posaconazole cause skeletal abnormalities in animal models. Treat ment of blastomycosis in pregnant patients consists of lipid ampho tericin B 3 5 mgkgday for 6 8 weeks. For patients receiving itraconazole, the oral antifungal of choice, therapeutic drug monitoring should be performed 14 days into ther apy (goal total itraconazole level 1 5 gmL), and liver function tests should be monitored periodically. Because of the long half life of itra conazole, serum drug levels can be obtained at any time of the day, irrespective of when the drug was administered. Total |
7,618 | itraconazole level is determined by adding itraconazole and hydroxyitraconazole concentrations; hydroxyitraconazole is a metabolite that possesses antifungal activity. Voriconazole, posaconazole, and isavuconazo nium sulfate have activity against B. dermatitidis. Clinical experience with these drugs is growing, and treatment outcomes are promis ing. Therapeutic drug monitoring is recommended for voriconazole and posaconazole (goal trough levels 1 5 gmL) and can be con sidered with isavuconazonium sulfate. The echinocandins (caspo fungin, micafungin, and anidulafungin) should not be used to treat blastomycosis. Serial measurement of urine antigen levels to assess response to therapy can be a helpful adjunct in monitoring response to antifungal therapy. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Coccidioidomycosis (valley fever, San Joaquin fever, desert rheuma tism, coccidioidal granuloma) is caused by Coccidioides spp., a soil dwelling dimorphic fungus. Coccidioides spp. grow in the environment as spore bearing (arthroconidia bearing) mycelial forms. In their parasitic form, they appear as unique, endosporulating spherules in infected tissue. The two recognized species, C. immitis and C. posadasii, cause clinically indistinguishable illnesses. EPIDEMIOLOGY Coccidioides spp. inhabit soil in arid regions. C. immitis is primar ily found in Californias San Joaquin Valley. C. posadasii is endemic to southern regions of Arizona, Utah, Nevada, New Mexico, western Texas, and regions of Mexico and Central and South America. The risk of infection among long term residents in endemic regions is 3 per year. Population migrations into endemic areas and increasing numbers of immunosuppressed persons have caused coccidioidomycosis to become an important health problem. From 2000 to 2012 in Califor nia, 4,582 cases, 1,301 hospitalizations, and 11 deaths associated with coccidioidomycosis were reported in children, who accounted for 9.2 of total cases. From 2015 to 2016, the rate of coccidioidomycosis cases among California children increased from 2.1 per 100,000 to 5.2 per 100,000. Case and hospitalization rates were highest in males and those 12 17 years. Another recent California study showed that 55 of chil dren were hospitalized, with a median length of stay of 44 days. Infection results from inhalation of aerosolized spores. Incidence increases during windy, dry periods that follow rainy seasons. Seismic events, archaeologic excavations, and other activities that disturb con taminated sites have caused outbreaks. Person to person transmission does not occur. Rarely, infections result from spores that contaminate fomites or grow beneath casts or wound dressings of infected patients. Infection has also resulted from transplantation of organs from infected donors and from mother to fetus. Visitors to endemic areas can acquire infections, and diagnosis may be delayed when they are evaluated in nonendemic areas. Spores are highly virulent, and Coccidioides spp. are potential agents of bioterrorism (see Chapter 763). PATHOGENESIS Inhaled spores reach terminal bronchioles, where they transform into septated spherules that resist phagocytosis and within which many endospores develop. Released endospores transform into new spher ules, and the process results in an acute focus of infection. Endospores can also disseminate lymphohematogenously. Eventually, a granulo matous reaction predominates. Both recovery and protection upon reexposure depend on effective cellular immunity. Children with congenital |
7,619 | primary immunodeficiency disorders may be at increased risk for infection; these disorders include interleukin 12R1 deficiency, interferon R1 deficiency, and STAT1 gain of function mutations. CLINICAL MANIFESTATIONS The clinical spectrum (Fig. 286.1) encompasses pulmonary and extrapulmonary disease. Pulmonary infection occurs in 95 of cases and can be divided into primary, complicated, and residual Chapter 286 Coccidioidomycosis (Coccidioides Species) Felicia A. Scaggs Huang and Rebecca C. Brady Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 286 u Coccidioidomycosis (Coccidioides Species) 1937 Primary Pulmonary Infection 60 40 Asymptomatic Infection (occasional residual pulmonary cavity, nodule) Symptomatic Infection 7585 Spontaneous recovery 510 Residual pulmonary disease (cavity or nodule) 510 Extrapulmonary dissemination Fig. 286.1 Natural history of coccidioidomycosis. infections. Approximately 60 of infections are asymptomatic. Symptoms in children are often milder than those in adults. The incidence of extrapulmonary dissemination in children approaches that of adults. Primary Coccidioidomycosis The incubation period is 1 4 weeks, with an average of 10 16 days. Early symptoms include malaise, chills, fever, and night sweats. Chest dis comfort occurs in 5070 of patients and varies from mild tightness to severe pain. Headache andor backache are sometimes reported. Eva nescent, generalized, fine macular, erythematous or urticarial eruptions may be seen within the first few days of infection. Erythema nodosum can occur (more often in females) and is sometimes accompanied by erythema multiforme, usually 3 21 days after the onset of symptoms. The clinical constellation of erythema nodosum, fever, chest pain, and arthralgias (especially knees and ankles) is called desert rheumatism and valley fever. Profound fatigue can occur and lasts weeks to months. Of note, extrapulmonary manifestations of a primary pulmonary infection do not necessarily represent disseminated disease. In hospi talized children, pulmonary symptoms are most common. The chest examination is often normal even if radiographic findings are present. Dullness to percussion, friction rub, or fine rales may be present. Pleu ral effusions can occur and can become large enough to compromise respiratory status. Hilar and mediastinal lymphadenopathy are com mon (Fig. 286.2). Complicated Pulmonary Infection Complicated infections include severe and persistent pneumonia, pro gressive primary coccidioidomycosis, progressive fibrocavitary disease, transient cavities that develop in areas of pulmonary consolidation, and empyema that follows rupture of a cavity into the pleural space. Some cavities persist, are thin walled and peripheral, and cause no symptoms; occasionally there is mild hemoptysis, and rarely there is serious hemorrhage. Rarely, acute respiratory insufficiency occurs after intense exposure; this condition is associated with high mortality rates. Residual Pulmonary Coccidioidomycosis Residual pulmonary coccidioidomycosis includes fibrosis and persist ing pulmonary nodules. Nodules are present in 57 of infections and sometimes require differentiation from malignancy in adults. Disseminated (Extrapulmonary) Infection Clinically apparent dissemination occurs in 0.5 of patients. Its inci dence is increased in infants; men; pregnant women who become infected during the second and third trimesters; persons of Filipino, African, and Latin |
7,620 | American ancestry; and persons from other Asian backgrounds. Primary or acquired disorders of cellular immunity (Table 286.1) markedly increase the risk of dissemination. A conve nience sample of 108 children in California reported that diagnosis occurred a median of 57 days after symptom onset in those with dis seminated infection (compared to 16 days in those with acute or pul monary coccidioidomycosis). Symptoms usually occur within 6 months of primary infection. Prolonged fever, toxicity, skin lesions, subcutaneous andor osse ous cold abscesses, and laryngeal lesions can herald the onset. Skin lesions have a predilection for the nasolabial area and appear initially as papules, which evolve to form pustules, plaques, abscesses, and verrucous plaques. Biopsy of these lesions demonstrates spherules. Basilar meningitis is the most common manifestation and may be accompanied by ventriculitis, ependymitis, cerebral vasculitis, abscess, and syringomyelia. Headache, vomiting, meningismus, and cranial nerve dysfunction are often present. Untreated meningitis is almost invariably fatal. Hydrocephalus is the most common compli cation in surviving patients. Bone infections account for 2050 of extrapulmonary manifestations, are often multifocal, and can affect adjacent structures. Miliary dissemination and peritonitis can mimic tuberculosis. Fig. 286.2 Chest radiograph of a 19 yr old male with acute primary coccidioidomycosis. There is prominent hilar lymphadenopathy and mediastinal widening. Table 286.1 Risk Factors for Poor Outcome in Patients with Active Coccidioidomycosis PRIMARY INFECTIONS Severe, prolonged (6 wk), or progressive infection RISK FACTORS FOR EXTRAPULMONARY DISSEMINATION Primary or acquired cellular immune dysfunction (including patients receiving tumor necrosis factor inhibitors or high dose glucocorticoids) Neonates, infants, the elderly Male sex (adult) Filipino, African, Native American, or Latin American ethnicity Late stage pregnancy and early postpartum period Standardized complement fixation antibody titer 1:16 or increasing titer with persisting symptoms Blood group B Human leukocyte antigen class II allele DRBI1301 Diabetes mellitus Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1938 Part XV u Infectious Diseases DIAGNOSIS Nonspecific tests have limited usefulness. Most routine laboratory evaluations are unremarkable. Complete blood count might show an elevated eosinophil count; marked eosinophilia can accompany dis semination. As a result, a high index of suspicion is required to direct an appropriate workup, especially in patients who have visited or reside in an endemic area. Culture, Histopathologic Findings, and Antigen Detection Any isolation of Coccidioides spp. from a patient specimen is consid ered definitive evidence of infection because the fungus is not part of the normal human microbiome. However, although diagnostic, culture is positive in only 8.3 of respiratory tract specimens and in 3.2 of all other sites. It may take several days for a specimen to grow. Coc cidioides spp. is isolated from clinical specimens as the spore bearing mold form, and thus the laboratory should be informed and use spe cial precautions when the diagnosis is suspected. Inappropriate bio containment procedures can lead to infection of exposed laboratory staff. The observation |
7,621 | of endosporulating spherules in histopathologic specimens using potassium hydroxide (KOH) preparations, calcofluor white, or hematoxylin and eosin (HE) stains is diagnostic. Periodic acid Schiffor Gomorimethenamine silver stains also may be used to demonstrate the fungus. A quantitative enzyme immunoassay (EIA) (MiraVista Diagnos tics, Indianapolis, IN) that detects coccidioidal galactomannan in urine, serum, plasma, cerebrospinal fluid (CSF), or bronchoalveolar lavage fluid has excellent specificity and is positive in 70 of patients with severe infections. Although the EIA can cross react with other endemic mycoses, interpretation is often straightforward because there is negligible geographic overlap with areas endemic for other mycoses. In addition, a real time polymerase chain reaction (PCR) assay has been developed to directly detect the fungus in tissue sam ples. The specificity is high, but sensitivity is not greater than that of routine cultures. Presently, Coccidioides spp. PCR is available through reference laboratories. CSF analysis should be performed in patients with suspected dissemination. Findings in meningitis are similar to those seen with tuberculous meningitis (see Chapter 261). Eosinophilic pleocytosis may be present. Fungal stains and culture are usually negative. Volumes of 10 mL in adults have improved the yield of culture. Serology Serologic tests provide valuable diagnostic information but may be falsely negative early in self limited infections and in immunocom promised patients. Three major methods are used, including EIA, complement fixation (CF), and immunodiffusion. EIA and CF tests are best done in experienced reference laboratories because false positive results may be reported. Immunoglobulin (Ig) Mspecific antibody becomes measurable in 50 of infected patients 1 week after onset and in 90 of infected patients by 3 weeks. EIA is sensitive and can detect IgM and IgG antibody. It is less specific than other methods; confirmation with immunodiffusion or CF may be needed. IgG antibodies measured by CF appear between the second and third week but can take several months; follow up testing is needed if tests are negative and clinical suspicion persists. In the presence of CF titers of 1:2 or 1:4, a positive immunodiffusion test can help corroborate significance because it is less sensitive but more specific than EIA. IgG specific antibody can persist for months, with titers elevated in proportion to the sever ity of illness. CF titers 1:16 are suggestive of dissemination. Direct comparison of the results of CF (IgG) antibody tests measured by different methodologies should be interpreted with caution. IgG anti body titers used to monitor disease activity should be tested concur rently with serum samples taken earlier in the illness using the same methodology. C. immitis antibody is present in CSF in 95 of patients with men ingitis and is usually diagnostic. Rarely, spillover in patients without meningitis but with high IgG titers in serum can be present in CSF. Iso lation of Coccidioides spp. from CSF culture of patients with meningitis is uncommon, although culture of large volumes of CSF may improve sensitivity. Imaging Procedures During primary infection, chest radiography may be normal or dem onstrate consolidation, single or multiple circumscribed lesions, |
7,622 | or soft pulmonary densities. Pulmonary infiltrates in the upper lobes are more common in coccidioidal infection than in classic bacterial pneumonia. Hilar and subcarinal lymphadenopathy is often present (see Fig. 286.2). Cavities tend to be thin walled (Fig. 286.3). Pleural effusions vary in size. The presence of miliary or reticulonodular lesions is prognosti cally unfavorable. Isolated or multiple osseous lesions are usually lytic and affect cancellous bone. Lesions can affect adjacent structures, and vertebral lesions can affect the spinal cord. TREATMENT Based on the few rigorous clinical trials performed in adults and the opinions of experts in the management of coccidioidomycosis, consensus treatment guidelines have been developed (Table 286.2). A B Fig. 286.3 A, Chest radiograph revealing a chronic cavitary lesion in the right lung of a female with coccidioidomycosis. B, CT showing the same cavity in the right lung. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 286 u Coccidioidomycosis (Coccidioides Species) 1939 Consultation with experts in an area of endemicity should be consid ered when formulating a management plan. Many patients with mild primary coccidioidomycosis do not require antifungal therapy. How ever, those at risk of severe or complicated disease should receive treatment. Treatment is recommended for HIV infected patients with active coccidioidomycosis and CD4 counts 250L. After successful treat ment, antifungals may be stopped if the CD4 count exceeds 250L. Treatment should be continued if the CD4 count remains less than 250L and should be given indefinitely in all HIV infected patients with coccidioidal meningitis. Patients with other forms of chronic immunosuppression (e.g., solid organ transplant recipients) may also require lifelong therapy. First line agents include oral and intravenous preparations of fluco nazole (612 mgkg; max 4001200 mgday) and itraconazole (25 mg kg PO twice daily; max 400 mgday). Fluconazole is often the first line therapy because it has high bioavailability and few side effects. Serum concentrations of itraconazole should be monitored. Amphotericin B is preferred for initial treatment of severe infec tions. Amphotericin B deoxycholate is less costly than lipid formu lations and is often well tolerated in children. Once a daily dose of amphotericin B deoxycholate of 0.5 1.5 mgkgday is achieved, the frequency of administration can be reduced to 3 times weekly. The recommended total dosage ranges from 15 45 mgkg and is deter mined by the clinical response. Lipid formulations of amphotericin are recommended for patients with impaired renal function, for patients receiving other nephrotoxic agents, or if amphotericin B deoxycholate is not tolerated. Some experts prefer liposomal amphotericin to treat central nervous system infections because it achieves higher levels in brain parenchyma. Amphotericin B preparations do not cross the blood brain barrier to effectively treat Coccidioides spp., but they can mask the signs of meningitis. Infections during pregnancy should be treated with amphotericin B, because the azoles are potentially terato genic. Isavuconazole, voriconazole, and posaconazole |
7,623 | have been used successfully as salvage therapy. Primary Pulmonary Infection Primary pulmonary coccidioidomycosis resolves in 95 of patients without risk factors for dissemination; antifungal therapy does not lessen the frequency of dissemination or pulmonary residua. When it is elected to defer antifungal therapy, visits are recommended at 1 to 3 month intervals for 2 years and as needed. Patients with significant or prolonged symptoms are more likely to incur benefit from antifungal agents, but there are no established crite ria upon which to base the decision. Table 286.2 summarizes commonly used indicators in adults. A treatment trial in adults with primary respi ratory infections examined outcomes of antifungal therapy prescribed on the basis of severity and compared them with an untreated group with less severe symptoms; complications occurred only in patients in the treatment group and only in those in whom treatment was stopped. If treatment is elected, a 3 to 6 month course of fluconazole (12 mg kgday) or itraconazole (10 mgkgday) is recommended. Diffuse Pneumonia Diffuse reticulonodular densities or miliary infiltrates, sometimes accompanied by severe illness, can occur in dissemination or after exposure to a large fungal inoculum. In this setting, amphotericin B is recommended for initial treatment, followed thereafter by extended treatment with high dose fluconazole (see Table 286.2). Disseminated (Extrapulmonary) Infection For nonmeningeal infection (see Table 286.2), oral fluconazole and itraconazole are effective for treating disseminated coccidioidomycosis that is not extensive, is not progressing rapidly, and has not affected the central nervous system. Some experts recommend higher doses for adults than were used in clinical trials. A subgroup analysis showed a tendency for improved response of skeletal infections that were treated with itraconazole. Amphotericin B deoxycholate is used as an alterna tive, especially if there is rapid worsening and lesions are in critical locations. Voriconazole has been used successfully as salvage therapy. The optimal duration of therapy with the azoles has not been clearly defined. Late relapses have occurred after lengthy treatment and favor able clinical response. Meningitis Therapy with oral or IV fluconazole is currently preferred for coccidi oidal meningitis. In adults, a dosage of 400 1,200 mgday is recom mended. For children, the dose is 12 mgkgday. Some experts use intrathecal, intraventricular, or intracisternally administered ampho tericin B in addition to an azole, believing that the clinical response may be faster. Patients who respond to the azole should continue treatment indefinitely. Hydrocephalus is common and not necessarily a marker of treatment failure. In the event of treatment failure with azoles, intrathecal amphotericin B deoxycholate is indicated, with or without the azole. Cerebral vasculitis can occur and may predispose to cerebral ischemia, infarction, or hemorrhage. The efficacy of high dose steroids is unresolved. Salvage therapy with isavuconazole or voricon azole has been effective. Surgical Management If a pulmonary cavity is located peripherally or there is recurrent bleeding or pleural extension, excision may be needed. Infrequently, bronchopleural fistula or recurrent cavitation occurs as a surgical Table 286.2 Indications for Treatment of Coccidioidomycosis in Adults INDICATION TREATMENT |
7,624 | Acute pneumonia, mild Observe without antifungal treatment at 1 to 3 mo intervals for 2 yr; some experts recommend antifungal treatment Weight loss 10; night sweats 3 wk; infiltrates at least half of one lung or parts of both lungs; prominent or persistent hilar lymphadenopathy; complement fixation titers 1:16; inability to work, symptoms 2 mo Treat with an azole daily for 3 6 mo, with follow up at 1 to 3 mo intervals for 2 yr Uncomplicated acute pneumonia, special circumstances: immunosuppression, late pregnancy, Filipino or African ancestry, age 55 yr, other chronic diseases (diabetes, cardiopulmonary disease), symptoms 2 mo Treat with an azole daily for 3 6 mo, with follow up at 1 to 3 mo intervals for 2 yr Treat with amphotericin B if in late pregnancy Diffuse pneumonia: reticulonodular or miliary infiltrates suggest underlying immunodeficiency and possible fungemia Treat initially with amphotericin B if significant hypoxia or rapid deterioration, followed by an azole for 1 yr In mild cases, an azole for 1 yr Chronic pneumonia Treat with an azole for 1 yr Disseminated disease, nonmeningeal Treat with an azole for 1 yr except in severe or rapidly worsening cases, for which amphotericin B is recommended Disseminated disease, meningeal Treat with fluconazole (some add intrathecal amphotericin B) and treat indefinitely Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1940 Part XV u Infectious Diseases complication; rarely, dissemination can result. Perioperative intrave nous amphotericin B may be considered. Drainage of cold abscesses, synovectomy, and curettage or excision of osseous lesions are some times needed. Surgical consultation is appropriate if vertebral involve ment is identified to evaluate for spinal cord involvement. Local and systemic administration of amphotericin B can be used to treat coc cidioidal articular disease. Monitoring Patients should be followed closely because late relapses can occur despite treatment, especially in those who are immunosuppressed or have severe manifestations. Testing for CF antibodies should be obtained every 12 weeks during treatment. Most titers decline as the patient improves and ultimately become undetectable. However, titers may remain positive in recovered patients. Progressive or disseminated disease should be considered when titers are persistently elevated (1:32). These individuals may need thorough physical examinations and imaging studies. After completion of therapy, patients should be evaluated yearly for at least 2 years because some patients relapse (28 of adults who completed 12 months of fluconazole, 18 for itraconazole). Refractory Disease In patients who do not improve clinically on appropriate therapy, develop new symptoms, or have persistently elevated CF titers, investi gations are indicated for complicated and disseminated disease. Evalu ations should assess for joint effusions, skin lesions, and neurologic dysfunction. Consultation with a physician experienced in the man agement of coccidioidal infections should be considered. PREVENTION Prevention relies on education about ways to reduce exposure. Phy sicians practicing in nonendemic regions should incorporate careful travel histories when |
7,625 | evaluating patients with symptoms compatible with coccidioidomycosis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Paracoccidioidomycosis (South American or Brazilian blastomycosis, Lutz Splendore Almeida disease) is the most common systemic myco sis in Latin America. It is a fungal infection that is endemic in South America, with cases also reported in Mexico and Central America. Brazil accounts for more than 80 of all reported cases. The etiologic agent, Paracoccidioides brasiliensis, is a thermally dimorphic fungus found in the environment in the mycelial (mold) form and in tissues as yeast. EPIDEMIOLOGY P. brasiliensis is a soil inhabiting microorganism and is ecologically unique to Central and South America. Endemic outbreaks occur mainly in the tropical rainforests of Brazil, with cases scattered in Argentina, Colombia, and Venezuela. There is an increased incidence Chapter 287 Paracoccidioides brasiliensis Andrew P. Steenhoff in areas with moderately high altitude, with high humidity and rainfall, and where coffee and tobacco are grown. Armadillos appear to be a natural reservoir for P. brasiliensis. The most common route of infec tion is by inhalation of conidia. The disease is not usually thought to be contagious, and person to person transmission has not been con firmed. Paracoccidioidomycosis is more common among boys after puberty because of the role of estrogen in preventing the transition of conidia to the yeast form. Children account for 10 of the total num ber of cases. PATHOGENESIS Invasion of P. brasiliensis into the human body is based on a myriad of fungal components and strategies to bypass host defense mechanisms. With the emergence of CRISPR technology and full access to diverse databanks (such as genomes, transcriptomes, proteomes, metabo lomes, lipidomes), investigators are poised to better understand the virulence processes of P. brasiliensis, hopefully allowing translation into benefits for patients. The entry route into the body is via the respiratory tract, and the lungs are the site of primary infection, although not all patients have respiratory symptoms. Once the conidia or hyphal fragments reach the alveoli, yeast transformation takes place. The infection then spreads to the mucous membranes of the nose, mouth, and gastrointestinal tract. Cell mediated immunity, mainly through lymphocytes and the production of Th 1 cytokines, is crucial to containing the infection. Tumor necrosis factor and interferon activated macrophages are responsible for intracellular killing of P. brasiliensis. If the initial immune response is not successful, the response may shift toward a Th 2 pattern, which is unable to contain the infection, resulting in clinical progression. The yeast can disseminate by the lymphohematogenous route to skin, lymph nodes, and other organs and remain dormant in lymph nodes, pro ducing a latent infection with reactivation occurring later in life. There are cases of patients who developed disease 30 or more years after leaving an endemic region. Histopathologically, the yeastlike cells are round, with the parent cell being quite large and surrounded by small buds, giving it the appear ance of a ships wheel. A mixed suppurative and granulomatous inflam matory reaction with areas of necrosis is seen |
7,626 | in pulmonary infections. In chronic infections, fibrosis and calcification may be seen. Mucocuta neous infections are typified by ulceration and pseudoepitheliomatous hyperplasia. CLINICAL MANIFESTATIONS There are two clinical forms of disease. The acute form (juvenile paracoccidioidomycosis) is rare, occurs almost exclusively in chil dren and persons with impaired immunity, and targets the reticulo endothelial system. Pulmonary symptoms may be absent, although chest radiographs often show patchy, confluent, or nodular densi ties. Patients typically present acutely with fever, malaise, wasting, lymphadenopathy, and abdominal enlargement from intraabdominal lymphadenopathy. Hepatomegaly and splenomegaly are nearly con stant. Localized bony lesions have been reported in children and can progress to systemic disease. Multifocal osteomyelitis, arthritis, and pericardial effusions can also occur. Nonspecific laboratory findings include anemia, eosinophilia, and hypergammaglobulinemia. Acute paracoccidioidomycosis has a 25 mortality rate. Hepatic involve ment associated with jaundice and hypoalbuminemia may confer a worse prognosis. Adults develop a chronic progressive illness that manifests initially with flulike symptoms, fever, and weight loss (adult paracoccidioido mycosis). Pulmonary infection develops with dyspnea, cough, chest pain, and hemoptysis. Findings on physical examination are scant, although chest radiographs can show infiltrates that are disproportion ate with mild clinical findings. Mucositis involving the mouth and its structures as well as the nose can manifest as localized pain, change in voice, or dysphagia. Lesions can extend beyond the oral cavity onto the skin. Generalized lymphadenopathy, hepatosplenomegaly, and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 288 u Sporotrichosis (Sporothrix schenckii) 1941 adrenal involvement (seen in 1550 of cases) can lead to Addison disease. Meningoencephalitis and central nervous system granulomas can occur as presenting or secondary symptoms. Adults with extensive exposure to soil, such as farmers, are most likely to develop the chronic form of the disease. DIAGNOSIS Demonstration of the fungus by direct wet mount (potassium hydrox ide) preparation of sputum, exudate, or pus supports the diagnosis in many cases. Histopathologic examination of biopsy specimens using special fungal staining techniques is also diagnostic. Immunohisto chemistry using monoclonal antibodies to specific glycoproteins can also be done on tissue sections. Culture of the fungus on Sabouraud dextrose or yeast extract agar confirms the diagnosis. Antibodies to P. brasiliensis can be demonstrated in most patients. Serial antibody titers and lymphocyte proliferative responses to fungal antigens are useful for monitoring the response to therapy. The 43 kDa glycopro tein (gp43) is present in sera of more than 90 of patients with para coccidioidomycosis by immunodiffusion (the most commonly used diagnostic test) and in 100 of patients by immunoblotting. A latex particle agglutination test using pooled crude fungal exoantigens is being developed for the detection of antiP. brasiliensis antibodies and has shown 92 agreement with the immunodiffusion test. Newer diagnostic methods that might prove to be very useful in the future include polymerase chain reaction, detection of gp43, and capture enzyme linked immunosorbent assay to detect |
7,627 | specific immuno globulin E in patient sera. Skin testing with paracoccidioidin is not reliable, because 3050 of patients with active disease are nonreac tive initially, and a positive test indicates previous exposure but not necessarily active disease. TREATMENT Itraconazole (5 10 mgkgday with a maximum dose of 200 mg day) orally for 6 months is the treatment of choice for paracoc cidioidomycosis. Fluconazole has also been used, but high doses (600 mgday) and longer treatment periods are required. A small number of patients have been treated with other azoles, including voriconazole, posaconazole, and isavuconazole. These drugs are potential substitutes for itraconazole but are more costly and can have interactions with other drugs. Terbinafine is an allylamine that has potent in vitro activity against P. brasiliensis and has been used for successful treatment of paracoccidioidomycosis. Ampho tericin B is recommended for disseminated disease and if other therapies fail. Therapy with sulfonamide compounds, including sulfadiazine, TMP SMX (trimethoprim 8 10 mgkgday to maxi mum of 160 mg, sulfamethoxazole 40 50 mgkgday to maximum of 800 mg), and dapsone, have been used historically and are gen erally less expensive than the newer azoles and allylamines. The primary disadvantage is that the treatment course is very long, lasting months to years, depending on the agent selected. Relapse can occur after any form of therapy, including with amphotericin B. In selected patients with intense inflammation in sites such as the central nervous system or with lung lesions causing respiratory insufficiency, there is some evidence that use of prednisone for 1 2 weeks concomitantly with antifungal therapy reduces inflamma tion more effectively and may be of benefit. Occasionally children develop paradoxical clinical worsening during treatment, including new lymph node enlargement, fistula formation, fever, and weight loss. In this circumstance, steroids are also recommended. Two therapies currently under investigation include the use of curcumin, an antioxidant found in the Indian spice turmeric, and the calcineurin inhibitor cyclosporine. Curcumin was found to have more antifungal activity than fluconazole against P. brasiliensis when studied in vitro using human buccal epithelial cells. Cyclosporine blocks the thermodimorphism of P. brasiliensis. Animal models dem onstrate that fungal whole cells, purified antigens, peptides, and DNA vaccines have great potential toward the development of a vaccine for use in humans. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Sporotrichosis is a rare fungal infection that occurs worldwide, both sporadically and in outbreaks, and is caused by Sporothrix schenckii, which exhibits temperature dimorphism, existing as a mold at environ mental temperatures (2530C 7786F) and as a yeast in vivo (37C 98.6F). S. schenckii comprises a group of cryptic, phylogenetically related species, including S. brasiliensis, S. chilensis, S. globosa, S. luriei, S. mexicana, and S. pallida. S brasiliensis is the most virulent species. EPIDEMIOLOGY S. schenckii is found throughout the world, but most cases of sporotri chosis are reported from South America, Central America, and Asia, including Japan, India, and China. In the United States, the majority of cases have occurred in the Midwest, particularly in |
7,628 | areas along the Mississippi and Missouri rivers. The fungus is found in decaying veg etation and has been isolated most commonly from sphagnum moss, rosebushes, barberry, straw, and some types of hay. Sporotrichosis can occur as an occupational disease among farmers, gardeners, veterinar ians, and laboratory workers. Transmission from bites and scratches of animals, most commonly cats and armadillos, has occurred. Reports of human to human transmission are rare. Sporotrichosis has rarely been reported in infants. The mechanism of transmission in children may be zoonotic but usually is unclear. In one endemic area of Peru, the inci dence of infection is greater in children than in adults; risk factors for infection in these children are playing in crop fields, living in houses with dirt floors, and owning a cat. PATHOGENESIS Disease in humans usually follows cutaneous inoculation of the fungus into a minor wound. Pulmonary infection can result from the inhala tion of large numbers of spores. Disseminated infection is unusual but can occur in immunocompromised patients after ingestion or inhala tion of spores. The cellular immune response to S. schenckii infection is both neutrophilic and monocytic. Histologically, the coexistence of noncaseating granulomas and microabscess formation is character istic. T cellmediated immunity appears to be important in limiting infection, and antibody does not protect against infection. As a result of the paucity of organisms, it is usually difficult to demonstrate the fungi in biopsy specimens. CLINICAL MANIFESTATIONS Cutaneous sporotrichosis is the most common form of disease in all age groups. Cutaneous disease may either be lymphocutaneous or fixed cutaneous, the former being much more common (Fig. 288.1). Lymphocutaneous sporotrichosis accounts for more than 75 of reported cases in children and occurs after traumatic subcutaneous inoculation. After a variable and often prolonged incubation period (1 12 weeks), an isolated, painless erythematous papule develops at the inoculation site. The initial lesion is usually on an extremity in adults but is often on the face in children. The original papule enlarges and ulcerates. Although the infection might remain limited to the inocula tion site (fixed cutaneous form), satellite lesions follow lymphangitic spread and appear as multiple tender subcutaneous nodules tracking along the lymphatic channels that drain the lesion. These secondary nodules are subcutaneous granulomas that adhere to the overlying skin and subsequently ulcerate. Sporotrichosis does not heal spontaneously, and these ulcerative lesions can persist for years if untreated. Systemic signs and symptoms are uncommon. Chapter 288 Sporotrichosis (Sporothrix schenckii) Andrew P. Steenhoff Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1942 Part XV u Infectious Diseases Fig. 288.1 Sporotrichosis. Erythematous papules and nodules on the plantar surface with early lymphangitic (sporotrichoid) spread. (From Paller AS, Mancini AJ. Hurwitz Clinical Pediatric Dermatology, 5th ed. Philadelphia: Elsevier; 2016: Fig. 17.48.) Extracutaneous sporotrichosis is rare in children, and most cases are reported in adults with underlying medical conditions, including AIDS |
7,629 | and other immunosuppressing diseases. The most common form of extracutaneous sporotrichosis involves infection of the bones and joints. Pulmonary sporotrichosis usually manifests as a chronic pneu monitis similar to the presentation of pulmonary tuberculosis. Ery thema nodosum is an immunoreactive manifestation. DIAGNOSIS Cutaneous and lymphocutaneous sporotrichosis must be differentiated from other causes of nodular lymphangitis, including atypical myco bacterial infection, nocardiosis, leishmaniasis, tularemia, melioidosis, cutaneous anthrax, and other systemic mycoses, including coccidioi domycosis. Definitive diagnosis requires isolation of the fungus from the site of infection by culture. Special histologic staining such as peri odic acidSchiff and methenamine silver is required to identify yeast forms in tissues, which are typically oval or cigar shaped. In spite of special staining techniques, diagnostic yield from biopsy specimens is low because of the small number of organisms present in the tissues. In cases of disseminated disease, demonstration of serum antibody against S. schenckiirelated antigens can be diagnostically useful. Sero logic testing is not commercially available but is offered by specialized laboratories, including the Centers for Disease Control and Prevention in the United States. TREATMENT Although comparative trials and extensive experience in children are not available, itraconazole is the recommended treatment of choice for infections outside the central nervous system. The recommended dosage for children is 5 10 mgkgday orally, with an initial maximum dose of 200 mg daily, which may be increased up to 400 mg daily if there is no initial response. Alternatively, younger children with cutaneous disease only may be treated with a saturated solution of potassium iodide (1 drop, 3 times daily by mouth, increasing as tol erated to a maximum of 1 dropkg of body weight or 40 50 drops, 3 times daily, whichever is lowest). Adverse reactions, usually in the form of nausea and vomiting, should be managed with temporary cessation of therapy and reinstitution at a lower dosage. Therapy is continued 2 4 weeks after cutaneous lesions have resolved, which usually takes at least 6 12 weeks. Terbinafine has been used successfully to treat cuta neous sporotrichosis but is reported to have lower cure rates and higher relapse rates than itraconazole. Further clinical efficacy data are needed to routinely recommend its use. Amphotericin B is the treatment of choice for pulmonary infections, disseminated infec tions, central nervous system disease, and infections in immuno compromised persons. Oral fluconazole 12 mgkg daily (maximum dose, 400 800 mg daily) can be used if other agents are not tolerated. Posaconazole shows promise, but further data are needed. Therapy with azoles or a saturated solution of potassium iodide should not be used in pregnant women. Amphotericin B can be used safely for cases of pulmonary or disseminated disease in pregnancy. Pregnant patients with cutaneous disease can be treated with local hyperthermia or can have therapy delayed until the pregnancy is com pleted. Hyperthermia involves heating the affected area to 4245C (107.6113F) using water baths or heating pads and works by inhibit ing growth of the fungus. Dissemination to the fetus does not occur, |
7,630 | and the disease is not worsened by pregnancy. Surgical debridement has a role in the treatment of some cases of sporotrichosis, particu larly in osteoarticular disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Mucormycosis refers to opportunistic invasive fungal infections caused by fungi of the order Mucorales. These organisms are found commonly in soil and decaying organic matter and are distributed worldwide. Mucormycosis was previously called zygomycosis, but this terminology has been abandoned because of reclassification of organisms using molecular phylogenetic analysis. The most com mon disease causing genera of Mucorales are Rhizopus, Mucor, and Lichtheimia (formerly Absidia). Infections caused by organisms of the genera Rhizomucor, Cunninghamella, Saksenaea, Apophysomy ces, and others are less common. Mucormycosis in humans is char acterized by a rapidly evolving course, tissue necrosis, and blood vessel invasion. EPIDEMIOLOGY Mucormycosis is primarily a disease of persons with underlying con ditions that impair host immunity, though it can sometimes mani fest with cutaneous and soft tissue infections at sites of trauma in immunocompetent hosts. Predisposing factors include poorly con trolled diabetes, especially if complicated by ketoacidosis, and pro found immunocompromise resulting from therapy for hematologic malignancies (especially with prolonged neutropenia), stem cell or organ transplantation, andor high dose corticosteroid therapy. Other risk factors include iron overload and prematurity. Mucor mycosis may develop as a breakthrough infection in patients receiv ing voriconazole antifungal prophylaxis; voriconazole lacks activity against the Mucorales. Therefore breakthrough infections or non response to voriconazole should prompt increased consideration of mucormycosis. Mucormycosis is the second most common invasive mold infection in immunocompromised hosts after aspergillosis, and its incidence is increasing because of an increase in the number and improved survival of immunocompromised persons at risk. A contemporary review of reported pediatric cases from 2008 to 2017 found a 32 case fatality rate across all included cases. Mortality rates vary depending on dis ease manifestations of mucormycosis and underlying patient condi tions, with worse outcomes observed in patients with more extensive disease manifestations and those with irreversible predisposing risk factors. However, observational studies suggest that pediatric patients with mucormycosis generally have more favorable outcomes compared to adults and that outcomes may be improving over time with contem porary therapeutic approaches. Chapter 289 Mucormycosis Rachel L. Wattier and William J. Steinbach Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 289 u Mucormycosis 1943 PATHOGENESIS Spores can be inhaled from the environment into the upper andor lower airways, inoculated at sites of cutaneous trauma, or, less com monly, ingested. If, because of impaired immune response, spores are not cleared by macrophages and neutrophils, they germinate into hyphae, resulting in local invasion and tissue destruction. Mucormy cosis is characterized by extensive angioinvasion, resulting in throm bosis, infarction, and tissue necrosis, which can limit the delivery of antifungal agents and leukocytes to the site of infection and contribute to dissemination of the |
7,631 | infection to other organs. Many of the Mucorales can scavenge iron, an element essential for cell growth, from the host. The iron chelator deferoxamine paradoxi cally increases iron availability and uptake by members of the Muco rales. Acidosis diminishes the phagocytic and chemotactic ability of neutrophils while increasing the availability of unbound iron, likely explaining the susceptibility to mucormycosis among individuals with uncontrolled acidosis. CLINICAL MANIFESTATIONS Mucormycosis can occur as any of several clinical syndromes, including rhinocerebral, pulmonary, cutaneous or subcutaneous, gastrointestinal, or disseminated disease. The initial symptoms and signs of each may be subtle and not easily distinguishable from other infections, so it is impor tant to have a high index of suspicion for the disease in patients at risk. Rhinocerebral mucormycosis is the most common form and can involve the palate, sinuses, orbit, andor adjacent structures with potential progression to the brain. Initial symptoms are similar to sinusitis and include headache, retroorbital pain, fever, and nasal dis charge. Infection can evolve rapidly or be slowly progressive. Orbital involvement manifests as periorbital edema, proptosis, ptosis, and or ophthalmoplegia. The nasal discharge may be dark and bloody; involved tissues become red, then violaceous, and then black as vessel thrombosis and tissue necrosis occur. Extension beyond the nasal cav ity into the mouth is common and may be apparent as palatal lesion(s). Destructive paranasal sinusitis with bone involvement and possible intracranial extension can be demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI) (Fig. 289.1). Rhinocere bral mucormycosis can be complicated by cavernous sinus thrombosis or thrombosis of the internal carotid artery. Intracranial extension can occur directly from the nasal cavity and sinuses, usually to the frontal or frontotemporal lobes, or hematogenously, commonly involving the occipital lobe or brainstem. Pulmonary mucormycosis usually occurs in profoundly neutrope nic patients and presents similarly to other pulmonary invasive mold infections. Manifestations can include fever, tachypnea, productive cough, pleuritic chest pain, and hemoptysis; however, initial symp toms may be minimal. A wide range of pulmonary radiographic find ings, including pulmonary nodules, consolidation, cavitary lesion(s), and lung infarct(s), are recognized (see Fig. 289.1). Although the radiographic findings overlap with other pulmonary invasive fungal infections, the presence of multiple nodules (10), pleural effusion(s), or the reverse halo sign, a focal area of ground glass opacity surrounded by a ring of consolidation, is more suggestive of mucormycosis. Cutaneous and soft tissue mucormycosis can be primary, result ing from direct inoculation at sites of trauma, including burns, surgical sites, or vascular access sites, or secondary, resulting from hematog enous dissemination to the skin from another primary site. Primary cutaneous lesions manifest initially as painful erythematous papules that ulcerate, leaving a black necrotic center. In contrast, secondary cutaneous lesions from hematogenous seeding tend to be nodular, with minimal destruction of the epidermis. Either may be invasive locally, progressing through multiple tissue layers, including muscle, fascia, and bone (Fig. 289.2), with accompanying tissue necrosis. Gastrointestinal mucormycosis is the least common form of dis ease except in preterm neonates, in whom |
7,632 | it is the most commonly reported form of mucormycosis. Manifestations include abdominal pain, nausea, vomiting, gastrointestinal bleeding, obstruction, and perforation. Any part of the gastrointestinal tract can be involved, with the stomach followed by colon and ileum being the most commonly A B C D Fig. 289.1 Radiographic findings in mucormycosis. A, CT scan shows left maxillary sinus air fluid level, similar to bacterial sinusitis. B, Magnetic resonance image reveals T2 signal hyperintensity in the left pterygoid musculature (arrow) in conjunction with a left maxillary sinus air fluid level. C, Multiple heterogeneous nodular and consolidative lesions with a large pulmonary vessel infarct and modest pleural effusions are shown in a patient with cancer and pulmonary mucormycosis. D, Contrast enhanced CT scan demonstrates a cavity within a dense infiltrate in a patient with acute my elogenous leukemia and pulmonary mucormycosis. (Courtesy Dr. Edith Marom, University of Texas, MD Anderson Cancer Center, Houston, Texas.) Fig. 289.2 Cutaneous presentation of mucormycosis. Chronic, non healing ulcer with necrosis after traumatic inoculation. (From Kontoyian nis DP, Lewis RE. Agents of mucormycosis and entomophthoramycosis. In Bennett JF, Dolin R, Blaser MJ (eds). Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Else vier, 2015. Fig. 2606A; Courtesy Drs. Gerald Bodey and Saud Ahmed, University of Texas, MD Anderson Cancer Center, Houston, TX.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1944 Part XV u Infectious Diseases affected. The clinical presentation in neonates mimics necrotizing enterocolitis, sometimes with a palpable abdominal mass. Recognition of gastrointestinal mucormycosis is challenging given its rarity and overlap in presentation with other gastrointestinal diseases. It is asso ciated with particularly high mortality and commonly not diagnosed until postmortem examination. Disseminated mucormycosis can develop from any site of primary disease but is more commonly associated with initial pulmonary dis ease. It carries the highest mortality rates seen with mucormycosis, especially among immunocompromised persons. The clinical presen tation varies based on the involved sites. Dissemination of mucormy cosis to the brain is of particular concern and alters management and prognosis, so many experts recommend brain imaging routinely, even in the absence of neurologic symptoms. DIAGNOSIS All forms of mucormycosis are considered medically emergent, and some (e.g., rhinocerebral) are also surgical emergencies. Diagnostic evaluation and initiation of treatment should be pursued simultane ously with a coordinated multidisciplinary approach. The diagnosis depends on early recognition of compatible clinical findings in a patient with predisposing risk factors. Once mucormycosis is suspected, cross sectional imaging should be performed to define the site(s) of disease as indicated based on the clinical presentation, and tissue from the site of disease should be obtained for diagnostic evaluation, along with initial surgical debridement for rhinocerebral or cutaneous mucormycosis. The diagnosis relies on direct morphologic identification of mycotic elements from culture or tissue biopsy specimens. Mucorales appear as broad (5 25 m in |
7,633 | diameter), infrequently septate (denoted as aseptate or pauci septate on pathology), thin walled hyphae, branching irregu larly at right angles when stained with Gomori methenamine silver (GMS) or hematoxylin and eosin. Organisms may be challenging to identify reliably by morphology from tissue specimens; immunohis tochemistry or molecular diagnostic tests can provide more reliable identification to the species level. Mucorales can be cultured on standard laboratory media; however, cultures from nontissue specimens, such as bronchoalveolar lavage fluid, have poor sensitivity. Mucorales hyphae can also be easily dis rupted, decreasing the yield of cultures. Submitting fresh tissue with careful handling to avoid disruption (e.g., grinding) can improve yield. When an organism is visualized by histopathology but not recovered in culture, molecular methods may improve detection. Though Mucora les can be culture contaminants, isolation in a susceptible host should prompt consideration of clinical disease. Noninvasive fungal biomark ers, such as galactomannan and 1,3 d glucan, do not detect the caus ative agents of mucormycosis. Though molecular tests are available to detect Mucorales and other fungal pathogens directly from blood samples, these have not yet been sufficiently validated to replace tissue based diagnosis. TREATMENT Though mucormycosis can be aggressive and difficult to treat, with high mortality rates, more favorable outcomes can be achieved via early recognition and prompt institution of medical therapy combined with extensive surgical debridement of devitalized tissue to the extent possible. It is essential to reverse predisposing factors, such as neutro penia, hyperglycemia, andor acidosis, and to withdraw immunosup pression or deferoxamine therapy, if applicable. Given the rarity of mucormycosis, there are few clinical trials to guide optimal therapy. Based on clinical experience, observational data, and small clinical trials, the European Confederation of Medical Microbiology and the Mycoses Study Group published global guide lines for mucormycosis in 2019. Lipid formulations of amphotericin B, with preference for liposomal amphotericin B, are strongly rec ommended as first line therapy for all forms of mucormycosis in all age groups. It is recommended to initiate therapy with the full dose of liposomal amphotericin B of at least 5 mgkgday, with consideration up to 10 mgkgday, and 10 mgkgday is recommended for treatment of central nervous system infection. Other antifungals with activity against the Mucorales include isavuconazole (administered as the pro drug isavuconazonium sulfate) and posaconazole; however, there is less experience with these antifungals for initial or primary therapy of mucormycosis, and their activity can vary based on causative species and specific antifungal susceptibility patterns. Guidelines moderately recommend primary therapy with IV formulations of either posacon azole or isavuconazole in patients with significant preexisting renal impairment, because of potential nephrotoxicity with amphotericin B formulations. However, some experts prefer liposomal amphotericin B for patients with severe or progressive mucormycosis even in the set ting of renal impairment. There is increasing pharmacokinetic and safety data support ing the use of isavuconazole and posaconazole in pediatric patients, though posaconazole pharmacokinetics vary by formulation, and the immediate release oral suspension does not reliably achieve optimal target concentrations. Therefore IV or |
7,634 | delayed release formulations of posaconazole are preferred. Isavuconazole or posaconazole is rec ommended for specific roles in the treatment of mucormycosis, the most established role being for salvage therapy in patients who either do not respond adequately to initial amphotericin Bbased therapy or who develop intolerance precluding continuation of amphotericin B based therapy. In the case of inadequate response, many experts recommend combination therapy, including liposo mal amphotericin B with either isavuconazole or posaconazole, so that the backbone therapy with liposomal amphotericin B can also be continued. Given the rapidly progressive course and severe out comes associated with mucormycosis, primary combination therapy (a regimen with multiple antifungal agents from the beginning) is also frequently used in practice. However, there is currently insufficient evidence to determine whether initial combination therapy is benefi cial over monotherapy with liposomal amphotericin B. The results of animal model studies and observational clinical studies have varied, and some of the better quality observational studies have not shown a clear benefit. Combination therapy with liposomal amphotericin B and isavuconazole or posaconazole is therefore marginally rec ommended in the global mucormycosis guidelines. Some clinicians have given combination therapy with an echinocandin antifungal (e.g., caspofungin) added to amphotericin Bbased therapy based on animal model data and limited clinical studies showing potential benefit with this combination. However, this combination has been less preferred recently, partly because echinocandins lack intrinsic activity against the Mucorales and because increasing data favor isavuconazole or posaconazole for salvage therapy. Given the complex considerations when selecting and monitoring antifungal therapy for mucormycosis, and also considering surgical approaches, which are well established for rhinocerebral and cutane ous mucormycosis and favored when possible for localized pulmonary mucormycosis, a multidisciplinary approach with expert guidance is necessary. Patients with mucormycosis should be monitored with fre quent repeat imaging to evaluate their response to therapy, and multiple surgical procedures are often necessary to achieve stabilization of disease. The duration of antifungal therapy is individualized but is usually continued until all clinical and radiographic findings have resolved and the patient shows reconstitution or significant improvement of their immune response. Patients with a good response to initial IV antifun gal therapy may be converted to maintenance therapy with enteral isa vuconazole or posaconazole. Various adjunctive therapies have been reported for mucormycosis; the most commonly used are treatments such as hematopoietic growth factors to reverse neutropenia as a predisposing factor. Hyperbaric oxygen has been used anecdotally as an adjunctive therapy but is not well established and not routinely recommended. Iron chelation with deferasirox has been tried as salvage therapy in refractory mucormy cosis but is currently not recommended because of adverse outcomes in a small clinical trial. The overall emphasis of disease management should remain on optimizing the antifungal and surgical therapies and reversing any modifiable predisposing conditions. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. |
7,635 | Elsevier Inc. All rights reserved. Chapter 290 u Pneumocystis jirovecii 1945 Pneumocystis jirovecii pneumonia (interstitial plasma cell pneumoni tis) in an immunocompromised person is a life threatening infection. Primary infection in the immunocompetent individual is usually sub clinical and goes unrecognized. The disease most likely results from new or repeat acquisition of the organism rather than reactivation of latent organisms. Even in the most severe cases, with rare exceptions, the pathogen remains localized to the lungs. ETIOLOGY The genus Pneumocystis contains a group of common extracellular fungal pathogens, which are found worldwide and exist exclusively in the lungs of mammalian hosts as obligate biotrophs. The initial taxonomic placement of Pneumocystis was ambiguous. However, com parative genomics definitively positioned Pneumocystis among the ascomycetous fungi, despite sharing certain morphologic features and drug susceptibility profiles with protozoa. Detailed information on the basic biology and life cycle of Pneumocystis is incomplete because of the inability to grow these organisms in culture. However, phenotypic and genotypic analyses show that the Pneumocystis organisms infecting each individual mammalian host are unique and restricted to that host. Cur rent knowledge suggests that a distinct Pneumocystis evolved in each host species and ultimately adapted to its specific host in a manner that prevented transmission and replication in heterologous host species. The clear biological distinction of Pneumocystis from different mam malian hosts led to the division of Pneumocystis into multiple species that are named according to the host from which they are derived. Cur rent convention uses the name P. jirovecii to refer to the Pneumocystis species infecting humans, whereas those infecting rats and mice are designated P. carinii and P. murina, respectively. Clinicians should be aware that the term P. carinii was originally used for all Pneumocystis regardless of host species of origin and may sometimes refer to human derived Pneumocystis in older medical literature. EPIDEMIOLOGY P. jirovecii is found worldwide, but a natural habitat outside of the human host has not been identified. Serologic surveys show that most humans are exposed to P. jirovecii before 4 years of age, and polymerase chain reaction (PCR) analyses has confirmed the prevalence of P. jir ovecii in both children and adults. Full genome sequencing of three Pneumocystis species, including P. jirovecii, revealed that Pneumo cystis has lost critical genes required for autonomous survival and growth. Thus currently available evidence suggests that P. jirovecii only lives in the lungs of humans and that it persists in the human popula tion through repeat subclinical or mild infection of immunocompetent adults and children. Gene loss helps to explain the inability to either culture Pneumocystis or identify a natural reservoir outside the host. The universal prevalence of P. jirovecii in the human population likely explains why P. jirovecii is a common opportunistic infection in immu nocompromised people not receiving prophylaxis. The mode of Pneumocystis transmission to humans is undefined, but animal to animal airborne transmission has been clearly demon strated. Animal to human transmission is unlikely because of the strin gent host species restriction of |
7,636 | Pneumocystis species. Person to person transmission is likely but has not been directly proven. However, the appearance of geographically clustered Pneumocystis cases caused by genetically similar P. jirovecii strains supports the occurrence of com munity spread among immunocompromised patients. In addition, P. jirovecii has been detected in air samples collected in close proximity to patients with Pneumocystis pneumonia. Thus it seems likely that P. jirovecii is passed from human to human through an airborne route. Most humans are infected with P. jirovecii during early childhood. In the immunocompetent child, these infections are usually asymp tomatic or mild and indistinguishable from other common childhood respiratory infections. Pneumonia caused by P. jirovecii occurs almost exclusively in severely immunocompromised hosts, including those with congenital or acquired immunodeficiency disorders, malignan cies, or transplanted organs. Patients with primary immunodeficiency diseases at risk for infection include severe combined immunodefi ciency disease, X linked CD40 ligand deficiency, major histocompat ibility complex class II deficiency, nuclear factor kappa B essential modulator (NEMO) deficiency, dedicator of cytokinesis 8 (DOCK8) deficiency, Wiskott Aldrich syndrome, and caspase recruitment domain 11 (CARD11) deficiency. P. jirovecii can be found in the lungs of infants who have died with the diagnosis of sudden infant death syndrome (SIDS). However, further study concluded that P. jirovecii is likely not the cause of SIDS but instead that there is overlap in the tim ing of the primary P. jirovecii infection and the onset of SIDS. Recent studies have described pathologic changes in the lungs of infants dur ing primary infection and have suggested a possible association of P. jirovecii with respiratory distress syndrome in preterm infants. Without chemoprophylaxis, approximately 40 of infants and children with AIDS, 70 of adults with AIDS, 12 of children with leukemia, and 10 of patients with organ transplants develop P. jir ovecii pneumonia. Epidemics that occurred among debilitated infants in Europe during and after World War II are attributed to malnutri tion. Currently, the use of novel immunosuppressive agents for the treatment of inflammatory syndromes, autoimmune disease, and malignancy has expanded the at risk population. For example, the addition of antitumor necrosis factor (TNF) therapy to the man agement of patients with inflammatory bowel disease or rheumatoid arthritis has resulted in a demonstrable increase in P. jirovecii pneumo nia in these patient populations. The use of rituximab or ibrutinib in patients with hematologic malignancies also increases the risk of Pneu mocystis pneumonia. PATHOGENESIS Two forms of P. jirovecii are found in the alveolar spaces: the cyst form (or ascus), which are 5 8 m in diameter and contain up to eight pleo morphic intracystic bodies (sporozoites or ascospores); and trophic forms (or trophozoites), which are 2 5 m cells derived from excysted sporozoites. The names sporozoite and trophozoite were based on the morphologic similarities to protozoa. However, the inclusion of Pneu mocystis among the fungi led to the adoption of names such as ascus and ascospore, which are derived from fungal terminology. The cyst form accounts for 510 of the Pneumocystis in |
7,637 | the lung. The cyst has a thick wall composed of glucan, which is thought to be a major driver of pulmonary inflammation during Pneumocystis pneumonia. P. jirovecii trophic forms typically constitute approximately 90 of the Pneumocystis in the lungs and have the ability to suppress inflamma tion induced by the cyst form. Trophic forms attach firmly to the type 1 pneumocytes lining the alveoli, possibly by adhesive bridging proteins such as fibronectin or mannose dependent ligands. The consequences of this interaction are unclear, but it may provide signals or nutrients to Pneumocystis to stimulate growth. As the infection progresses, this interaction may contribute to the characteristic alveolar damage. Control of P. jirovecii infection in immunocompetent people requires functional cell mediated immunity, and patients with AIDS show an increased incidence of Pneumocystis pneumonia as CD4 T lymphocyte counts decrease. Before widespread prophylaxis of AIDS patients, life threatening Pneumocystis pneumonia occurred in a high percentage of these patients when CD4 T cell counts dropped below 200 cellsmm3. CD4 T cell counts provide a useful indica tor in both older children and adults of the need for prophylaxis against Pneumocystis pneumonia. Although normally functioning CD4 T cells are central to controlling P. jirovecii infection, the final effector pathway for destruction of P. jirovecii is poorly understood but likely requires macrophages. CD4 T cells may activate macrophages for phagocytosis and clearance of Pneumocystis through local cytokine secretion, and also provide help for the production of specific antibody. Chapter 290 Pneumocystis jirovecii Francis Gigliotti and Terry W. Wright Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1946 Part XV u Infectious Diseases Anti Pneumocystis antibody has the potential to facilitate fungal clear ance through opsonization, complement activation, or interfering with Pneumocystis binding to lung epithelial cells. Clinical investigation as well as work in animal models has revealed that the hosts immune response to Pneumocystis infection is a major contributor to the pathogenesis of Pneumocystis pneumonia. Human studies found that the severity of disease correlates with the degree of lung inflammation but not with fungal burden. Furthermore, patients with profound AIDS related immunosuppression present with higher P. jirovecii burdens but better lung function than non AIDS patients with Pneumocystis pneumonia and with greater retained immune func tion. A classic AIDS related presentation of Pneumocystis pneumonia can be modeled in CD4 T celldepleted rodents and simian immune virusinfected nonhuman primates. In the absence of CD4 T cells a progressive accumulation of CD8 T cells occurs in a likely attempt to fight the infection. These cells do not provide effective host defense against Pneumocystis, but instead directly contribute to Pneumocystis pneumoniarelated immunopathogenesis and lung injury. Similar to humans with Pneumocystis pneumonia, polymorphonuclear leuko cytes (PMNs) also accumulate in the lungs of animals as Pneumocystis pneumonia progresses. These phagocytes do not contribute mean ingfully to either Pneumocystis eradication or immunopathogenesis. However, as is |
7,638 | the case in human patients, there is a strong correlation between the number of PMNs in the lung and the severity of disease. In the complete absence of an adaptive immune response, as can be modeled in severe combined immunodeficient (SCID) mice, Pneumo cystis infection produces little alteration in lung histology or function until late in the course of the disease. However, if congenic lymphocytes are transferred to Pneumocystis infected SCID mice, an acute CD4 T celldependent immune response is mounted against the Pneumo cystis. There is rapid onset of pulmonary inflammation, surfactant dysfunction, severe respiratory impairment, and significant hypoxia, mimicking the characteristic changes of Pneumocystis pneumonia in humans. The functional CD4 T cells generate an effective immune response against the existing infection, but also cause inflammation and lung injury. CD8 T cells are typically ineffective in the eradication of Pneumocystis but may modulate the CD4 T cell response to lessen the immune mediated damage. The functional interactions of T cell subsets in patients with differing and often fluctuating immune sta tus are likely responsible for the variations in presentation and out come of Pneumocystis pneumonia. PATHOLOGY The histopathologic features of P. jirovecii pneumonia are of two types. The first type is infantile interstitial plasma cell pneumonitis, which was observed in epidemic outbreaks in debilitated infants 3 6 months of age. Extensive infiltration with thickening of the alveolar septum occurs, and plasma cells are prominent. The second type is a diffuse desquamative alveolar pneumonitis found in immunocompromised children and adults. The alveoli contain large numbers of P. jirovecii in a foamy exudate with alveolar macrophages active in the phagocytosis of organisms. The alveolar septum is not infiltrated to the extent it is in the infantile type, and plasma cells are usually absent. CLINICAL MANIFESTATIONS There are at least three distinct clinical presentations of P. jirovecii pneumonia. In patients with profound congenital immunodeficiency or in AIDS patients with very few CD4 T cells, the onset of hypoxia and symptoms is subtle and often without fever, with tachypnea pro gressing to nasal flaring; intercostal, suprasternal, and infrasternal retractions; and cyanosis in severe cases. In children and adults with immunodeficiency resulting from immunosuppressive medications, the onset of hypoxia and symptoms is often more abrupt, with fever, tachypnea, dyspnea, and cough, progressing to severe respiratory com promise. This type accounts for the majority of cases, although the severity of clinical expression can vary. Rales are usually not detected on physical examination. The third pattern of Pneumocystis pneumo nia is reported in severely immunocompromised patients who appear to be responding to therapy but then have an acute and seemingly paradoxical deterioration thought to be associated with the restoration of immune function. This condition is referred to as immune reconsti tution inflammatory syndrome and is most commonly seen in patients with newly diagnosed AIDS who present with P. jirovecii pneumonia and who have a rapid response to antiretroviral therapy that is insti tuted at the same time as anti Pneumocystis therapy. It can also occur in |
7,639 | stem cell transplant recipients who engraft while infected with P. jirovecii. LABORATORY FINDINGS AND DIAGNOSIS The chest radiograph reveals bilateral diffuse interstitial or alveolar ground glass infiltrates (Fig. 290.1). The earliest densities are perihilar, and progression proceeds peripherally, sparing the apical areas until last. The arterial oxygen tension (Pao2) is invariably decreased. The major role of the laboratory in establishing a diagnosis of P. jirovecii pneumonia is to identify organisms in lung specimens by a variety of methods. Definitive diagnosis requires visualization of P. jirovecii in the lung in the presence of clinical signs and symptoms of the infection. Organisms can be detected in specimens collected by bron choalveolar lavage (BAL), tracheal aspirate, transbronchial lung biopsy, bronchial brushings, percutaneous transthoracic needle aspiration, and open lung biopsy. Hypertonic salineinduced sputum samples are helpful if P. jirovecii is found, but the absence of the organisms in induced sputum does not exclude the infection and BAL should be performed. Open lung biopsy is the most reliable method, although BAL is more practical in most cases. Estimates of the diagnostic yield of the various specimens are 2040 for induced sputum, 5060 for tracheal aspirate, 7595 for BAL, 7585 for transbronchial biopsy, and 90100 for open lung biopsy. Once obtained, the specimens are typically stained with one of four commonly used stains: Grocott Gomori silver stain and toluidine blue stain for the cyst form, polychrome stains such as Giemsa stain for the trophic forms and ascospores, and the fluorescein labeled monoclonal antibody stains for both trophic forms and cysts. Many clinical labo ratories have adopted polymerase chain reaction analysis of respi ratory specimens for the diagnosis of Pneumocystis pneumonia. Serum lactate dehydrogenase (LDH) levels are often elevated during Pneumocystis pneumonia, and although elevated LDH is not a specific or definitive diagnosis, high levels should raise suspicion. A B C Fig. 290.1 Pneumocystis jirovecii infection in a 17 yr old male with acute lymphoblastic leukemia and immunodeficiency, who presented with dyspnea, fever, nonproductive cough, and decreased white blood cell counts. A, Radiograph shows diffuse bilateral interstitial opacity throughout the lungs. B, Contrast enhanced computed tomography confirms the bilateral patchy and ground glass opacities in both lungs. The diagnosis was confirmed by a positive polymerase chain reaction test from bronchial lavage fluid. C, CT in a different patient demon strates a typical crazy paving pattern in both upper lobes. (From Westra SJ, Yikilmaz A, Lee EY. Pulmonary infection. In: Coley BD, ed. Caffeys Pediatric Diagnostic Imaging, 13th ed. Philadelphia: Elsevier; 2019: Fig. 54.30.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 291 u Other Pathogenic Fungi 1947 TREATMENT The recommended therapy for P. jirovecii pneumonia is trimethoprim sulfamethoxazole (TMP SMX) (15 20 mg TMP and 75 100 mg SMX kgday in four divided doses) administered intravenously or orally if there is mild disease and no malabsorption or diarrhea. The duration |
7,640 | of treatment is 3 weeks for patients with AIDS and 2 weeks for other patients. Unfortunately, adverse reactions often occur with TMP SMX, especially rash and neutropenia in patients with AIDS. For patients who cannot tolerate or who fail to respond to TMP SMX after 5 7 days, pentamidine isethionate (4 mgkgday as a single dose IV) may be used. Adverse reactions are frequent and include renal and hepatic dysfunction, hyperglycemia or hypoglycemia, rash, and thrombocy topenia. Atovaquone (750 mg twice daily with food, for patients 13 years of age) is an alternative treatment that has been used primarily in adults with mild to moderate disease. Limited experience is available for younger children. Pharmacokinetic studies of atovaquone show that a dose of 30 mgkgday PO in two divided doses for children 0 3 months of age and older than 2 years of age is adequate and safe; a dose of 45 mgkgday PO in two divided doses is needed for children between 4 months and 2 years of age. Other effective therapies include trimetrexate glucuronate or combinations of trimethoprim plus dap sone or clindamycin plus primaquine. The combination of caspofungin and TMP SMX is also being assessed as a treatment for Pneumocystis pneumonia and may help control inflammation in some patients. Some studies in adults suggest that administration of corticoste roids as adjunctive therapy to suppress the inflammatory response increases the chances for survival in moderate and severe cases of P. jirovecii pneumonia. The recommended regimen of corticosteroids for adolescents older than 13 years of age and for adults is oral prednisone, 80 mgday PO in two divided doses on days 1 5, 40 mgday PO once daily on days 6 10, and 20 mgday PO once daily on days 11 21. A reasonable regimen for children is oral prednisone, 2 mgkgday for the first 7 10 days, followed by a tapering regimen for the next 10 14 days. SUPPORTIVE CARE Basic supportive care is dictated by the condition of the patient, with careful attention to maintain appropriate hydration and oxygenation. Only 510 of patients with AIDS require mechanical ventilation compared with 5060 of patients without AIDS, consistent with the hypothesis that the patients ability to mount an immuneinflammatory response correlates with severity and outcome of Pneumocystis pneu monia. There are anecdotal reports of giving surfactant to children with severe P. jirovecii pneumonia, although the use of surfactant to treat adult type respiratory distress syndrome is controversial. COMPLICATIONS Most complications occur as adverse events associated with the treat ment drugs or as a consequence of mechanical ventilation. The most severe pulmonary complication of P. jirovecii pneumonia is adult type respiratory distress syndrome. Rarely, P. jirovecii infection affects extra pulmonary sites (e.g., retina, spleen, and bone marrow), but such infec tions are usually not symptomatic and also respond to treatment. PROGNOSIS Without treatment, P. jirovecii pneumonitis is fatal in almost all immunocompromised hosts within 3 4 weeks of onset. The mortal ity rate varies with patient population and is related to |
7,641 | inflamma tory response rather than organism burden. Patients with AIDS have a mortality rate of 510, and patients with other diseases such as malignancies have mortality rates as high as 2025. Patients who require mechanical ventilation have mortality rates of 6090. Patients remain at risk for P. jirovecii pneumonia as long as they are immunocompromised. Continuous prophylaxis should be initi ated or reinstituted at the end of therapy for patients with AIDS (see Chapter 322). PREVENTION Patients at high risk for P. jirovecii pneumonia should be placed on chemoprophylaxis. Prophylaxis in infants born to HIV infected mothers and for HIV infected infants and children is based on age and CD4 cell counts (see Chapter 322). Because CD4 counts fluctu ate rapidly during the first year of life, infants born to HIV infected mothers should be placed on prophylaxis during the first year of life until HIV infection is ruled out. Patients with severe combined immu nodeficiency disease, patients receiving intensive immunosuppressive therapy for cancer or other diseases, and organ transplant recipients are also candidates for prophylaxis. TMP SMX (5 mgkg TMP and 25 mg SMXkg PO once daily or divided into two doses daily) is the drug of choice and may be given for 3 consecutive days each week or, alternatively, each day. Alternatives for prophylaxis include dap sone (2 mgkgday PO, maximum: 100 mgdose; or 4 mgkg PO once weekly, maximum: 200 mgdose), atovaquone (30 mgkgday PO for infants 1 3 months and 24 months of age; 45 mgkgday for infants and toddlers 4 23 months of age), and aerosolized pentamidine (300 mgmo by Respirgard II nebulizer), but all of these agents are inferior to TMP SMX. Finally, limited clinical experience suggests that pent amidine can be given intravenously once monthly to prevent P. jirove cii pneumonia. Prophylaxis must be continued as long as the patient remains immunocompromised. Some patients with AIDS who recon stitute adequate immunity during highly active antiretroviral therapy may have prophylaxis withdrawn. Recent animal studies suggest that vaccines may be effective at preventing Pneumocystis pneumonia in immunocompromised hosts, but to date none have been tested in humans. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Less common fungi that were once innocent or only contaminants are now emerging as lethal pathogens in a world of increasingly immu nocompromised patients. Although there are reports of countless previously considered nonpathogenic fungi infecting severely immu nocompromised patients, this chapter focuses on the most common and relevant miscellaneous fungi causing disease. PHAEOHYPHOMYCOSIS: CLADOPHIALOPHORA BANTIANA, BIPOLARIS SPP., AND OTHERS Phaeohyphomycosis is a heterogeneous group of fungal species com monly found in the soil and characterized by dematiaceous (darkly pig mented brown or black) hyphal forms in tissue. This staining can help distinguish between Aspergillus infections, and hyphae often appear more fragmented that seen with Aspergillus infections. The character istic color of the hyphae is related to the presence of melanin in the fungal cell wall, which likely plays a role in fungal pathogenesis. Phaeo comes from Greek, meaning dark, and has |
7,642 | been commonly used to describe infections with these fungi as phaeohyphomycosis. It has been suggested that the term dematiaceous is not appropriate given its ety mologic derivation from the Greek deme, meaning bundle, although it has become fairly entrenched in medical mycologic literature. The term melanized is also used, given its specific meaning. Phaeohyphomycosis has been attributed to more than 150 species of fungi. Among the most prevalent causes of human infection are Alter naria alternata, Acrophialophora fusispora, Aureobasidium pullulans, Bipolaris spp., Curvularia spp., Chaetomium spp., Cladophialophora Chapter 291 Other Pathogenic Fungi William J. Steinbach Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1948 Part XV u Infectious Diseases bantiana, Exserohilum, Fonsecaea, Hortaea werneckii, Neoscytalidium dimidiatum, Verruconis gallopava (previously Ochroconis gallopava), Phaeoacremonium, Phoma, Pyrenochaeta, Rhinocladiella, Veronaea botryosa, Wangiella dermatitidis (previously Exophiala dermatitidis), and Phialophora spp. In the multicenter CDC funded epidemiologic TRANSNET study, 26 cases of phaeohyphomycosis were identified in hematopoietic stem cell transplant (HSCT) recipients analyzed, representing 2.6 of all reported invasive fungal disease in the HSCT cohort. The median time from transplant to diagnosis was 100 days, and 92 of cases were seen in allogeneic HSCT recipients. The mortality rate was 42 at 90 days after diagnosis. There was a higher incidence of phaeohyphomycosis noted from transplant centers in the southern United States versus other regions of the country. Phaeohyphomycosis also represented 2.5 of the overall number of invasive fungal disease in solid organ transplant (SOT) recipients in the TRANSNET study. The median time from transplant to diagnosis was much longer at 18 months, and 53 of cases were specifically diagnosed in lung transplant recipients. There was a 10 mortality rate at 90 days after diagnosis. Overall, cutane ous disease was more common in SOT recipients, whereas pulmo nary disease was more common in hematopoietic stem cell transplant recipients. In this series, bloodstream and central nervous system (CNS) infections were seen only in hematopoietic stem cell transplant recipients. Historically, organisms causing phaeohyphomycosis have been largely associated with cutaneous and subcutaneous infections occur ring mostly in immunocompetent persons in tropical and subtropical regions. However, they have emerged with increasing frequency as causes of invasive disease in immunocompromised persons world wide. Infections can manifest as a range of clinical entities, including localized cutaneous infection and subcutaneous nodules, mycetomas (localized infections involving the cutaneous and subcutaneous tissue, fascia, and bone, often of the lower extremities, and characterized by mycotic granules), chromoblastomycosis (sclerotic bodies in tissues usually seen in tropical regions), keratitis, pulmonary infections, local ized deep infections, cerebral abscesses, disseminated infection, aller gic fungal sinusitis, and allergic bronchopulmonary mycosis. C. bantiana is the etiology for the majority of CNS phaeohypho mycosis, including patients that may have no apparent immunosup pression. CNS disease commonly presents with a headache and a focal neurologic deficit, frequently a hemiparesis, or seizures. The most common CNS manifestation is a solitary |
7,643 | brain abscess. Though the pathophysiology is not well understood, these are thought to originate via hematogenous dissemination from occult pulmonary or cutaneous foci. Diagnosis of phaeohyphomycosis relies on pathologic examina tion of cultures and biopsies, often with expert gross and microscopic examination required. There are no serologic or antigen tests to detect these fungi in blood or tissue, and PCR is in its infancy for this group of organisms. Almost all allergic disease and eosinophilia is caused by either Bipolaris spp. or Curvularia spp. Treatment Treatment recommendations for the rare molds causing phaeohy phomycosis are unfortunately primarily based on in vitro susceptibil ity data, case reports, and expert opinion. Recommendations can be found in European and Australian guidelines and the American Trans plant Society Infectious Diseases Community of Practice Guidelines. European antifungal treatment guidelines highlight the sparse data on preferred therapy, including in vitro data, limited animal model stud ies, and expert opinion. There are no clearly defined standard thera pies, but the guideline panel generally recommended voriconazole, posaconazole, or itraconazole, because those agents demonstrate the most consistent in vitro antifungal activity against this group of fungi. Specifically, voriconazole is likely the best for CNS infections because of its excellent CNS penetration. For invasive infections, surgery is crucial to the overall treatment. For phaeohyphomycosis, there is substantial variability in susceptibility both between and within species of a given genus, making correct species identification and sus ceptibility testing especially critical in guiding therapy for these infec tions. Combination therapy is suggested in some circumstances for disseminated or CNS infection and for organisms for which no single agent has predictably favorable activity. Therapy for CNS infections with C. bantiana is often unsuccessful despite susceptibility of this organism to several antifungal agents, and it is unclear whether antifungal therapy alters outcome, because survival without complete abscess resection is exceedingly rare. Some experts recommend combination therapy, particularly for cases in which the abscess cannot be completely resected. Surgery is particu larly important for brain abscesses secondary to C. bantiana infection; regardless of host immune status and antifungal therapy, survival is extremely poor if the abscess is not completely resected. If an invasive mold infection is associated with an intravenous catheter or a perito neal dialysis catheter, removal of the catheter is recommended. Including only culture positive cases of CNS phaeohyphomycosis, the survival rate for this infection is only 35. A series of 30 cases revealed those patients with single, encapsulated CNS lesions did much better than those with multifocal disease. However, no patient who did not undergo surgery survived. Whether patients underwent neurosur gery alone or with antifungal therapy, the most important factor for cure was resectability of the lesion; antifungal therapy itself was not associated with improved survival. HYALOHYPHOMYCOSIS: FUSARIUM AND SCEDOSPORIUM SPP. AND OTHERS In contrast to phaeohyphomycosis, hyalohyphomycosis refers to infec tions caused by hyaline (colorless, nonpigmented, nonmelanized) septate fungal hyphae. The major hyalohyphomycotic pathogens are Fusarium spp., Scedosporium spp., Paecilomyces spp., Trichoderma spp., Acremonium spp., Scopulariopsis spp., and Purpureocillium spp. |
7,644 | These species are often misidentified as Aspergillus spp., but they can be differentiated by their conidia and phialide morphologies. This sec tion focuses on Fusarium and Scedosporium spp., which are usually the third and fourth most common invasive mold diseases in immuno compromised hosts, after invasive aspergillosis and mucormycosis. The majority of human cases of fusariosis are caused by members of the Fusarium solani, Fusarium oxysporum, and Fusarium fujikuroi spp. complexes, with the F. solani spp. complex demonstrating greater pathogenicity. Nomenclature of organisms causing scedosporiosis can be confusing and has undergone recent changes. The genus name Pseudallescheria applies to the sexual state (teleomorph) whereas Sce dosporium applies to the asexual state (anamorph) of these organisms. Scedosporium apiospermum was once thought to be the anamorph of Pseudallescheria boydii, but these organisms are now known to be distinct species. The S. apiospermum spp. complex encompasses S. apiospermum, Scedosporium boydii, Scedosporium aurantiacum, Sce dosporium dehoogii, and Scedosporium minutispora. The organism formerly known as Scedosporium prolificans is now renamed Lomen tospora prolificans and is phylogenetically distinct from the Scedospo rium spp. In addition to the usual airborne and cutaneous inoculation routes of acquisition common to other invasive molds, Fusarium can be trans mitted via contaminated water sources (e.g., shower heads) and can cause infection associated with intravenous catheters. Both Fusarium and ScedosporiumLomentospora spp. can cause infection in immu nocompetent hosts, primarily localized infections such as keratitis or onychomycosis. In immunocompromised patients, Fusarium can disseminate from initially localized infections such as onychomyco sis or intertrigo. The major predisposing factors for invasive disease are profound and prolonged neutropenia and severe cell mediated immunodeficiency. Among HSCT recipients in the TRANSNET study, fusariosis accounted for 3 of invasive fungal disease. Identified risk factors for fusariosis in HSCT recipients include history of cytomegalovirus infection, receipt of an umbilical cord blood transplant (compared with other stem cell sources), receipt of antithymocyte globulin, and Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 291 u Other Pathogenic Fungi 1949 hyperglycemia. Risk factors specific to development of fusariosis beyond day 40 after transplant include graft versus host disease and prior invasive mold disease. Scedosporiosis is less common among HSCT recipients compared with fusariosis, with only 16 cases identi fied in the TRANSNET study compared with 31 cases of fusariosis and 77 cases of mucormycosis. Among 1208 invasive fungal infections in the TRANSNET study of SOT recipients, there were 6 cases of fusari osis and 11 cases of scedosporiasis, compared with 28 cases of mucor mycosis. In a literature review of L. prolificans cases, SOT recipients constituted 8.6 of cases. Scedosporiasis is most common among lung transplant recipients, in whom colonization of the airways can occur pretransplantation (particularly in patients with cystic fibrosis), or posttransplantation, and may progress to invasive infection. Among patients undergoing therapy for cancer, fusariosis primarily occurs in those with hematologic malignancy, especially acute |
7,645 | myelogenous leu kemia. In a single center study of 44 cases, the most commonly identi fied risk factors for fusariosis in patients with hematologic malignancy were active leukemia, prolonged and profound neutropenia, and high dose corticosteroid exposure. Clinical Presentations The most common sites of invasive fusariosis in immunocompromised persons are the skin (6080 of cases), lungs (5080 of cases), and sinuses (2030 of cases). Fusarium can develop yeastlike adventitious sporulation within infected tissue, which facilitates dissemination, seen in 70 of cases. Unlike other molds that infrequently cause detectable fungemia and are difficult to recover in standard blood culture media, blood cultures are positive for Fusarium in 4050 of cases. Radiographic series comparing findings of pulmonary fusariosis to those of invasive aspergillosis and mucormycosis note that the halo sign (a nodule surrounded by ground glass opacity) is frequently absent in cases of fusariosis. Cutaneous lesions of invasive fusariosis are distinc tive, consisting of painful, circular macules or papules, usually with central necrosis and surrounding erythema. Appearance of cutaneous lesions in invasive fusariosis is usually secondary to hematogenous dis semination to the skin, rather than direct inoculation into the skin. Invasive disease caused by S. apiospermum spp. complex most fre quently involves the skin, lungs, and CNS. CNS disease develops in the context of hematogenous dissemination and can manifest as brain abscess(es) or meningoencephalitis. Other manifestations include sinusitis and endogenous endophthalmitis. Skin lesions of S. apio spermum spp. complex can manifest as nodules, erythematous or violaceous papules, or bullae, which may develop necrosis. They are usually secondary to hematogenous dissemination rather than primary cutaneous lesions from direct inoculation of the skin. Lymphangitic or sporotrichoid spreading patterns have been described. Blood cultures are positive in approximately 30 of cases of invasive infection with S. apiospermum spp. complex. Similar manifestations are seen in invasive L. prolificans infections, but the propensity to disseminate is higher and positive blood cultures are reported in over 50 of cases. Hematog enous dissemination of L. prolificans to the CNS is common. Diagnosis Diagnosis of fusariosis or scedosporiasis requires isolation and identifi cation of the causative organism from the affected site(s). The causative organisms have thin septate hyphae with acute angle branching; they are not morphologically distinguishable from Aspergillus when exam ined in tissue. Culture is necessary for definitive identification of these organisms, though distinguishing between Fusarium spp. complexes may be difficult using conventional methods. Organisms causing fusa riosis and scedosporiosis can be detected in conventional blood cul tures; however, they may be initially reported out as yeast because of the appearance of conidia produced by adventitious sporulation. The Aspergillus serum galactomannan assay is positive in approxi mately half of patients with invasive fusariosis and detection of serum galactomannan above threshold has been shown to precede diagnosis of invasive fusariosis in a high prevalence setting. Treatment Treatment recommendations for fusariosis and scedosporiasis are pro vided in European Society of Clinical Microbiology and Infectious Dis eases (ESCMID) and European Confederation of Medical Mycology (ECMM) joint guidelines, and in Australian consensus guidelines. |
7,646 | The optimal therapy is unknown; recommendations are primarily based on case reports, clinical experience, and in vitro data, given a lack of clinical trials for these rare diseases. The ESCMIDECMM guidelines recommend voriconazole or a lipid based amphotericin B formula tion for treatment of fusariosis, with preference for voriconazole. Australian guidelines do not state a preference for either agent on the basis of inadequate data. Voriconazole treatment has been associated with higher treatment responses and improved survival, though these should be interpreted with caution because of potential confounding by earlier diagnosis or other interventions. Because in vitro susceptibility of Fusarium isolates to both voricon azole and amphotericin B varies widely, some experts routinely use combination therapy with voriconazole and lipid based amphoteri cin B to ensure that at least one agent is active. Some reports describe successful combination therapy with terbinafine and either liposo mal amphotericin B or voriconazole, and in vitro data show synergy between terbinafine and voriconazole. Isavuconazole has been studied in few adult cases; based on in vitro susceptibilities it appears to be less active than voriconazole. Fusarium spp. are resistant to the echinocan dins and to itraconazole. The activity of antifungal agents against members of the S. apiosper mum spp. complex is variable, and there are species based differences in susceptibility pattern. Amphotericin Bbased therapy is not recom mended due to in vitro resistance and poor clinical responses. Voricon azole is the most active agent and the recommended first line therapy. In a large observational study, the response rate to voriconazole therapy for S. apiospermum infections was 66. The echinocandins, itracon azole, and posaconazole have variable activity. Isavuconazole is active in vitro but so far has been studied in only a handful of adults with scedosporiasis, limiting conclusions about its utility. L. prolificans is highly resistant to all antifungal agents currently available. Successful treatment of infections caused by this organism depends on reversal of predisposing conditions and aggressive sur gical debridement. Voriconazole is the antifungal with best demon strated activity, but minimum inhibitory concentrations tend to be high and clinical responses to voriconazole therapy are suboptimal. Combination therapy is typically used, including voriconazole and other agents; successful outcomes have been reported with vori conazole or posaconazole and terbinafine or voriconazole with an echinocandin. Australian guidelines recommend the combination of voriconazole with terbinafine. However, terbinafine is highly protein bound with distribution primarily to skin and adipose tissue, leading some experts to doubt its utility in treating systemic fungal infections. There have been reports of combination therapy including miltefo sine, which is typically used in the treatment of leishmaniasis but demonstrates some in vitro antifungal activity against L. prolificans. It is important to recognize that publication bias likely has an impact on reporting of outcomes and no particular antifungal regimen has convincing evidence to support efficacy against L. prolificans. Surgical debridement of infected and necrotic tissue is recom mended to facilitate cure, particularly in L. prolificans infection, for which surgery and immune reconstitution are the primary effec tive |
7,647 | therapies. Removal of intravenous catheters is recommended for catheter associated fusariosis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1950 Part XV u Infectious Diseases Antiviral chemotherapy typically requires a delicate balance between targeting critical steps in viral replication without interfering with host cellular function. Because viruses require cellular functions to com plete replication, many antiviral agents exert significant host cellular toxicity, a limitation that has hindered antiviral drug development. In spite of this limitation, a number of agents are licensed for use against viruses, particularly herpesviruses, respiratory viruses, and hepatitis viruses (Table 292.1). In making the decision to commence antiviral drugs, it is important for the clinician to obtain appropriate diagnostic specimens, which can help clarify the antiviral of choice. The choice of a specific antiviral is based on the recommended agent of choice for a particular clini cal condition, pharmacokinetics, toxicities, cost, and the potential for development of resistance (Table 292.2). Intercurrent conditions in the patient, such as renal insufficiency, should also be considered. Clini cians must monitor antiviral therapy closely for adverse events or tox icities, both anticipated and unanticipated. In vitro sensitivity testing of virus isolates to antiviral compounds usually involves a complex tissue culture system. The potency of an antiviral is determined by the 50 inhibitory dose (ID50), which is the antiviral concentration required to inhibit the growth in cell culture of a standardized viral inoculum by 50. Because of the complexity of these assays, the results vary widely, and the actual relationship between antiviral sensitivity testing and antiviral therapy outcomes is sometimes unclear. Because these assays are often not readily available and take considerable time to complete, genotypic analysis for antiviral susceptibility is increasingly being offered. Such assays may be useful for patients on long term anti viral therapy. Clinical context is essential in making decisions about antivi ral treatment, along with knowledge of a patients immune status. For example, antiviral treatment is rarely if ever indicated in an immunocompetent child shedding cytomegalovirus (CMV) but may be lifesaving when administered to an immunocompromised solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) patient. Antivirals can be used with a variety of clinical goals in mind. Antivirals can be used for treatment of active end organ disease, as prophylaxis to prevent viral infection or disease, or as preemptive therapy aimed at reducing risk of progression to disease (i.e., a positive signal indicating viral replication but in the absence of clinical evidence of end organ disease). In preemptive therapy, a patient will usually have a positive signal for polymerase chain reactionbased identification of viral nucleic acids in a clini cal sample (blood or body fluid) but have no symptoms. However, SOT and HSCT patients are at high risk of developing disease in this setting (particularly due to CMV infection), a scenario that |
7,648 | warrants preemptive treatment with an antiviral agent. In contrast, prophylaxis is administered to seropositive patients who are at risk to reactivate latent viral infection but do not yet have evidence of active viral replication or shedding. A fundamental concept important in the understanding of the mechanism of action of most antivirals is that viruses must use host cell components to replicate. Thus mechanisms of action for antiviral compounds must be selective to virus specific functions whenever possible, and antiviral agents may have significant toxicities to the host if these compounds impact cellular physiology. Some of the more com monly targeted sites of action for antiviral agents include viral entry, absorption, penetration, and uncoating (amantadine, rimantadine); transcription or replication of the viral genome (acyclovir, valacyclo vir, cidofovir, famciclovir, letermovir, maribavir, penciclovir, foscarnet, ganciclovir, valganciclovir, ribavirin, trifluridine); viral protein synthe sis (interferons IFNs) or protein modification (protease inhibitors); and viral assembly, release, or deaggregation (baloxavir, oseltamivir, peramivir, zanamivir, IFNs). An understudied and underappreciated issue in antiviral therapy is emergence of resistance, particularly in the setting of high viral load, high intrinsic viral mutation rate, and prolonged or repeated courses of antiviral therapy. Resistant viruses are more likely to develop or be selected for in immunocompromised patients because these patients are more likely to have multiple or long term exposures to an antiviral agent. ANTIVIRALS USED FOR HERPESVIRUSES The herpesviruses are important pediatric pathogens, particularly in newborns and immunocompromised children. Most of the licensed antivirals are nucleoside analogs that inhibit viral DNA polymerase, inducing premature chain termination during viral DNA synthesis in infected cells. Acyclovir Acyclovir is a safe and effective therapy for herpes simplex virus (HSV) infections. The favorable safety profile of acyclovir derives from its requirement for activation to its active form via phosphorylation by a viral enzyme, thymidine kinase (TK). Thus acyclovir can be acti vated only in cells already infected with HSV that express the viral TK enzyme, a strategy that maximizes selectivity and reduces the potential for cellular toxicity in uninfected cells. Acyclovir is most active against HSV and is also active against varicella zoster virus (VZV); therapy is indicated for infections with these viruses in a variety of clinical set tings. Activity of acyclovir against CMV is less pronounced, and activ ity against Epstein Barr virus is minimal, both in vitro and clinically. Therefore, under most circumstances, acyclovir should not be used to treat CMV or Epstein Barr virus infections. The biggest impact of acyclovir in clinical practice is in the treat ment of primary and recurrent genital HSV infections. Oral nucle oside therapy plays an important role in the management of acute primary genital herpes, treatment of episodic symptomatic reactiva tions, and prophylaxis against reactivation. Acyclovir is also indi cated in the management of suspected or proven HSV encephalitis in patients of all ages and for treatment of neonatal HSV infection, with or without central nervous system (CNS) involvement. With respect to neonatal HSV infection, the routine empirical use of acyclovir against presumptive or possible HSV |
7,649 | infection in infants admitted with fever and no focus in the first 4 weeks of life is controversial. Acyclovir should be used routinely in infants born to women with risk factors for primary genital herpes or infants presenting with any combination of vesicular lesions, seizures, meningoencephali tis, hepatitis, pneumonia, or disseminated intravascular coagulation. Some experts advocate the initiation of acyclovir in all febrile neo nates. Other experts have argued that a selective approach based on the history and physical examination is more appropriate when mak ing decisions about the use of acyclovir in febrile infants. Given the safety of the drug, prudence would dictate the use of acyclovir in such patients if HSV infection cannot be excluded. Acyclovir is indicated for the treatment of primary HSV gingivosto matitis and for primary genital HSV infection. Long term suppressive therapy for genital HSV and for recurrent oropharyngeal infections (herpes labialis) is also effective. Acyclovir is also recommended for Chapter 292 Principles of Antiviral Therapy Mark R. Schleiss Section 13 Viral Infections Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 292 u Principles of Antiviral Therapy 1951 Table 292.1 Currently Licensed Antiviral Drugs ANTIVIRAL TRADE NAME MECHANISM OF ACTIONCOMMENTS Acyclovir Zovirax Inhibits viral DNA polymerase Adefovir Hepsera Nucleotide reverse transcriptase inhibitor Amantadine Symmetrel Blocks M2 protein ion channel Baloxavir Xofluza Inhibits polymerase acidic endonuclease, blocking viral replication BMS 791325 Beclabuvir Inhibitor of HCV NS5B Evaluated in combination with asunaprevir and daclatasvir; active against HCV genotype 1 Boceprevir Victrelis Inhibitor of HCV NS3 serine protease Active against HCV genotype 1 Cidofovir Vistide Inhibits viral DNA polymerase Daclatasvir Daklinza Inhibitor of HCV NS5A Used in varying combinations with sofosbuvir, ribavirin, and interferon Dasabuvir Exviera Inhibitor of HCV NS5B Used together with the combination medication ombitasvir paritaprevirritonavir (Viekira Pak) Activity limited to HCV genotype 1 Elbasvir (Zepatier) Inhibitor of HCV NS5A Used in combination with the NS34A protease inhibitor grazoprevir under the trade name Zepatier, either with or without ribavirin Entecavir Baraclude Nucleoside reverse transcriptase inhibitor Active against HBV Famciclovir Generic Inhibits viral DNA polymerase Fomivirsen Vitravene Phosphorothioate oligonucleotide inhibits viral replication via antisense mechanism Foscarnet Foscavir Inhibits viral DNA polymerase and reverse transcriptase at pyrophosphate binding site Ganciclovir Cytovene Inhibits viral DNA polymerase Grazoprevir Zepatier Inhibitor of HCV NS3 4A serine protease Used in combination with elbasvir under the trade name Zepatier, either with or without ribavirin Idoxuridine Ophthalmic Herplex Inhibits viral DNA polymerase Interferon Intron A (interferon 2b) Roferon A (interferon 2a) Infergen (interferon alfacon 1) Produces multiple effector proteins that exert antiviral effects; also directly interacts with immune system components Interferon 2b plus ribavirin Rebetron Not established Lamivudine (3TC) Epivir Inhibits viral DNA polymerase and reverse transcriptase; active against HBV With dolutegravir, Dovato; with tenofovir, Delstrigo; with zidovudine, Combivir; with abacavir and dolutegravir, Triumeq. Ledipasvir (with Sofosbuvir: Harvoni) Inhibitor of HCV NS5A Letermovir Prevymis Prophylaxis against |
7,650 | CMV following HSCT Maribavir Livtencity Treatment of refractory CMV disease when treated with conventional antiviral therapy Molnupiravir Lagevrio Treatment of SARS CoV 2 Induces viral RNA mutations during replication Nirmatrelvirritonavir Paxlovid Treatment of SARS CoV 2 Protease inhibitor Ombitasvir (Viekira Pak) Inhibitor of HCV NS5A Used in combination with paritaprevir, ritonavir and dasabuvir in Viekira Pak Active against HCV genotype 1 Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1952 Part XV u Infectious Diseases Table 292.1 Currently Licensed Antiviral Drugscontd ANTIVIRAL TRADE NAME MECHANISM OF ACTIONCOMMENTS Oseltamivir Tamiflu Neuraminidase inhibitor; interference with deaggregation and release of viral progeny Paritaprevir (Viekira Pak) (TechnivieViekirax) Inhibitor of HCV NS3 4A serine protease Used in combination with ombitasvir, ritonavir and dasabuvir (Viekira Pak), or in combination with ombitasvir and ritonavir (TechnivieViekirax) Pegylated interferon PEG Intron (2b), Pegasys (2a) Same as interferon Penciclovir (topical) Denavir Inhibits viral DNA polymerase Peramivir Rapivab Neuraminidase inhibitor Remdesivir Veklury Treatment of SARS CoV 2 Inhibits viral RNA polymerase Ribavirin Virazole, Rebetol, Copegus Interference with viral messenger RNA Rimantadine Flumadine Blocks M2 protein ion channel Simeprevir Olysio Inhibitor of HCV NS3 4A serine protease Active against genotype 1 genotype 4 Used in combinations with sofosbuvir or ribavirin and pegylated interferon alfa Sofosbuvir (Harvoni) Inhibitor of HCV NS5B Used in combination with ledipasvir (Harvoni) Approved in children 6 years of age and 17 kg Telaprevir Incivek Incivo VX 950 Inhibitor of HCV NS3 4A serine protease Active against HCV genotype 1 No longer available in United States Telbivudine Tyzeka Interferes with HBV DNA replication No longer available in United States Tenofovir Viread Vemlidy Nucleoside reverse transcriptase inhibitor Active against HBV Trifluridine Viroptic Inhibits viral DNA polymerase Valacyclovir Valtrex Same as acyclovir Valganciclovir Valcyte Same as ganciclovir Velpatasvir (Epclusa, Sofosvel, Velpanat) Inhibitor of HCV NS5A Used in combination with sofosbuvir (Epclusa, Sofosvel, Velpanat) Active against all 6 HCV genotypes Vidarabine Ara A Inhibits viral DNA polymerase (and to lesser extent, cellular DNA polymerase) Zanamivir Relenza Neuraminidase inhibitor; interference with deaggregation and release of viral progeny FDA APPROVED COMBINATION THERAPIES WITH INTERFERONS Interferon 2b ribavirin Rebetron (Intron A plus Rebetol ribavirin) Discontinuation of Rebetol announced by FDA in 2019 Interferon 2a ribavirin Roferon A ribavirin Discontinuation of Roferon announced by manufacturer in 2020 Pegylated interferon 2b ribavirin (3 yr and older) PEG Intron PegIntron Sylatron ViraferonPeg PEG IntronRebetol (with ribavirin) Indicated for chronic hepatitis C Pegylated interferon 2a ribavirin (5 yr and older) Pegasys Copegus Approved for the treatment of chronic hepatitis C (in combination with ribavirin) and treatment of chronic hepatitis B (can be used alone) Has been used in the treatment of mycosis fungoides (a T cell lymphoma) No longer recommended by Centers for Disease Control and Prevention for treatment of influenza. No longer marketed in United States. No longer available. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com |
7,651 | by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 292 u Principles of Antiviral Therapy 1953 Table 292.2 Antiviral Therapies for Non HIV Clinical Conditions VIRUS CLINICAL SYNDROME ANTIVIRAL AGENT OF CHOICE ALTERNATIVE ANTIVIRAL AGENTS Influenza A and B Treatment Oseltamivir (2 wk old) Zanamivir (7 yr old) Peramivir (2 yr old) Baloxavir (12 yr old) Prophylaxis Oseltamivir (3 mo old) Zanamivir (5 yr old) Respiratory syncytial virus Bronchiolitis or pneumonia in high risk host Ribavirin aerosol COVID 19 Pneumonia MIS C Remdesivir Nirmatrelvirritonavir Molnupiravir Adenovirus In immunocompromised patients: Pneumonia Viremia Nephritis Hemorrhagic cystitis Cidofovir CMV Congenital CMV infection (symptomatic disease) Valganciclovir (long term oral valganciclovir may improve developmental and hearing outcomes) Ganciclovir Retinitis in AIDS patients Valganciclovir Ganciclovir Cidofovir Foscarnet Ganciclovir ocular insert Pneumonitis, colitis; esophagitis in immunocompromised patients Ganciclovir (IV) Foscarnet Cidofovir Valganciclovir Maribavir Prophylaxis for HSCT or SOT Acyclovir (high dose; oral) Valganciclovir Letermovir HSV Neonatal herpes Acyclovir (IV) Suppressive therapy following neonatal herpes Acyclovir (PO) HSV encephalitis Acyclovir (IV) HSV gingivostomatitis Acyclovir (PO) Acyclovir (IV) Valacyclovir (PO) First episode genital infection Acyclovir (PO) Valacyclovir Acyclovir (IV) (severe disease) Recurrent genital herpes Acyclovir (PO) Valacyclovir Suppression of genital herpes Acyclovir (PO) Valacyclovir Cutaneous HSV (whitlow, herpes gladiatorum) Acyclovir (PO) Penciclovir (topical) Eczema herpeticum Acyclovir (PO) Acyclovir (IV) (severe disease) Mucocutaneous infection in immunocompromised host (mild) Acyclovir (IV) Acyclovir (PO) (if outpatient therapy acceptable) Mucocutaneous infection in immunocompromised host (moderate to severe) Acyclovir (IV) HSV prophylaxis in bone marrow transplant recipients Acyclovir (IV) Valacyclovir Acyclovir resistant HSV Foscarnet Cidofovir Keratitis or keratoconjunctivitis Trifluridine Vidarabine Continued Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1954 Part XV u Infectious Diseases less commonly encountered HSV infections, including herpetic whit low, eczema herpeticum, and herpes gladiatorum. In addition, acyclo vir is commonly used for prophylaxis against HSV reactivation in SOT and HSCT patients. Severe end organ HSV disease, including dissemi nated infection, is occasionally encountered in immunocompromised or pregnant patients, representing another clinical scenario in which acyclovir therapy is warranted. Acyclovir modifies the course of primary VZV infection, although the effect is modest. Acyclovir or another nucleoside analog should always be used in localized or disseminated VZV infections in immu nocompromised patients. Primary VZV infection in pregnancy is another setting in which acyclovir is indicated; this is a high risk sce nario and can be associated with a substantial risk of maternal mortal ity, particularly if pneumonia is present. Acyclovir is available in topical (5 ointment), parenteral, and oral formulations, including an oral suspension formulation for pediatric use. Topical therapy has little role in pediatric practice and should be avoided in favor of alternative modes of delivery, particularly in infants with vesicular lesions compatible with herpetic infection, where topical therapy should never be used. The bioavailability of oral formulations is modest, |
7,652 | with only 1530 of the oral dose being absorbed. There is widespread tissue distribution after systemic administration, and high concentrations of drug are achieved in the kidneys, lungs, liver, myocar dium, and skin vesicles. Cerebrospinal fluid concentrations are approx imately 50 of plasma concentrations. Acyclovir crosses the placenta, and breast milk concentrations are approximately 3 times plasma con centrations, although there are no data on efficacy of in utero therapy or impact of acyclovir therapy on nursing infants. Acyclovir therapy in a nursing mother is not a contraindication to breastfeeding. The main route of elimination is renal, and dosage adjustments are necessary for renal insufficiency. Hemodialysis also eliminates acyclovir. Acyclovir has an exceptional safety profile. Toxicity is observed typi cally only in exceptional circumstances: for example, if administered by rapid infusion to a dehydrated patient or a patient with underly ing renal insufficiency, acyclovir can crystallize in renal tubules and produce a reversible obstructive uropathy. High doses of acyclovir are associated with neurotoxicity, and prolonged use can cause neutrope nia. The favorable safety profile of acyclovir is underscored by recent studies of its safe use during pregnancy, and suppressive therapy in pregnant women with histories of recurrent genital HSV infection, typ ically with valacyclovir (see later), has become standard of care among many obstetricians. One uncommon but important complication of long term use of acyclovir is the selection for acyclovir resistant HSV strains, which usually occurs from pathogenic variants in the HSV TK gene. Resistance is rarely observed in pediatric practice but should be considered in any patient who has been on long term antiviral therapy and who has an HSV or VZV infection that fails to clinically respond to acyclovir therapy. Valacyclovir Valacyclovir is the l valyl ester of acyclovir and is rapidly converted to acyclovir after oral administration. This agent has a safety and activity profile similar to that of acyclovir but has a bioavailability of 50, 3 5fold greater than that of acyclovir. Plasma concentrations approach those observed with intravenous acyclovir. Valacyclovir is available only for oral administration. A suspension formulation is not commercially available, but an oral suspension (25 mgmL or 50 mg mL) may be prepared extemporaneously from 500 mg caplets for use in pediatric patients for whom a solid dosage form is not appropri ate. Suppressive therapy with valacyclovir is commonly prescribed in the second and third trimesters of pregnancy in women who have a clinical history of recurrent genital herpes. It is important to be aware that perinatal transmission of HSV can occur, leading to symptomatic disease in spite of maternal antenatal antiviral prophylaxis. In such set tings, the possibility of emergence of acyclovir resistant virus should be considered. Penciclovir and Famciclovir Penciclovir is an acyclic nucleoside analog that, like acyclovir, inhibits the viral DNA polymerase after phosphorylation to its active form. Compared with acyclovir, penciclovir has a substan tially longer intracellular half life, which in theory can confer supe rior antiviral activity at the intracellular level; however, there is no evidence that |
7,653 | this effect confers clinical superiority. Penciclovir is licensed only as a topical formulation (1 penciclovir cream), and this formulation is indicated for therapy of cutaneous HSV infec tions. Topical therapy for primary or recurrent herpes labialis or cutaneous HSV infection is an appropriate use of penciclovir in children older than 2 years of age. Famciclovir is the prodrug formulation (diacetyl ester) of penciclo vir. After oral administration, famciclovir is deacetylated to the parent drug, penciclovir. The efficacy of famciclovir for HSV and VZV infec tions appeared equivalent to that of acyclovir, although the pharma cokinetic profile was more favorable. As of 2016, the drug has been discontinued. Ganciclovir and Valganciclovir Ganciclovir is a nucleoside analog with structural similarity to that of acyclovir. Like acyclovir, ganciclovir must be phosphorylated for anti viral activity, which is targeted against the viral polymerase. The gene responsible for ganciclovir phosphorylation is not TK but rather the virally encoded UL97 phosphotransferase gene. Antiviral resistance in CMV can be observed with prolonged use of nucleoside antivirals, and resistance should be considered in patients on long term therapy who appear to fail to respond clinically and virologically. Ganciclo vir is broadly active against many herpesviruses, including HSV and VZV, but is most valuable for its activity against CMV. Ganciclovir was Table 292.2 Antiviral Therapies for Non HIV Clinical Conditionscontd VIRUS CLINICAL SYNDROME ANTIVIRAL AGENT OF CHOICE ALTERNATIVE ANTIVIRAL AGENTS Varicella zoster virus Chickenpox, healthy child Supportive care Acyclovir (PO) Chickenpox, immunocompromised child Acyclovir (IV) Zoster (not ophthalmic branch of trigeminal nerve), healthy child Supportive care Acyclovir (PO) Zoster (ophthalmic branch of trigeminal nerve), healthy child Acyclovir (IV) Zoster, immunocompromised child Acyclovir (IV) Valacyclovir For antiviral agents for hepatitis B and hepatitis C, see Table 292.1. For MIS C, adjunctive therapies also include steroids, immunomodulatory therapy; see Chapter 449.1. CMV, Cytomegalovirus; HSV, herpes simplex virus. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 292 u Principles of Antiviral Therapy 1955 the first antiviral agent licensed specifically to treat and prevent CMV infection. It is indicated for prophylaxis against and therapy of CMV infections in high risk patients, including HIV infected patients and SOT or HSCT recipients. Of particular importance is the use of ganci clovir in the management of CMV retinitis, a sight threatening com plication of HIV infection. Ganciclovir is also of benefit for newborns with symptomatic congenital CMV infection and may be of value in partially ameliorating the sensorineural hearing loss and developmen tal disabilities that are common complications of congenital CMV infection. Ganciclovir is supplied in parenteral and oral (as the prodrug, val ganciclovir) formulations. Ganciclovir ocular implants are also avail able for the management of CMV retinitis. The bioavailability of oral ganciclovir is poor, 10, and therefore oral ganciclovir therapy has been supplanted by the oral prodrug valganciclovir, which is well absorbed from the gastrointestinal tract and quickly |
7,654 | converted to gan ciclovir by intestinal or hepatic metabolism. Bioavailability of ganciclo vir (from valganciclovir) is approximately 60 from tablet and solution formulations. Significant concentrations are found in the aqueous humor, subretinal fluid, cerebrospinal fluid, and brain tissue (enough to inhibit susceptible strains of CMV). Subretinal concentrations are comparable with plasma concentrations, but intravitreal concentra tions are lower. Drug concentrations in the CNS range from 24 to 70 of plasma concentrations. The main route of elimination is renal, and dosage adjustments are necessary for renal insufficiency. Dose reduction is proportional to the creatinine clearance. Hemodialysis efficiently eliminates ganciclovir, so administration of additional doses after dialysis is necessary. Ganciclovir has several important toxicities. Reversible myelosup pression is the most important toxicity and commonly requires either discontinuation of therapy or the intercurrent administration of granu locyte colonystimulating factor. There are also the theoretical risks of carcinogenicity and gonadal toxicity; although these effects have been observed in some animal models, they have never been observed in patients. The decision to administer ganciclovir to a pediatric patient is complex and should be made in consultation with a pediatric infec tious disease specialist. Foscarnet Foscarnet has a unique profile, insofar as it is not a nucleoside ana log but rather a pyrophosphate analog. The drug has broad activity against most herpesviruses. Like the nucleoside analogs, foscarnet inhibits viral DNA polymerase. On the other hand, foscarnet does not require phosphorylation to exert its antiviral activity, thus dif fering from the nucleoside analogs. It binds to a different site on the viral DNA polymerase to exert its antiviral effect and therefore retains activity against strains of HSV and CMV that are resistant to nucleo side analogs. Its clinical utility is as a second line agent for manage ment of CMV infections in high risk patients who cannot tolerate ganciclovir and as an alternative for patients with persistent or refrac tory HSV, CMV, or VZV disease with suspected or documented anti viral drug resistance. Foscarnet is available only as a parenteral formulation and is a toxic agent that must be administered cautiously. Nephrotoxicity is common, and reversible renal insufficiency is often observed, as evidenced by an increase in serum creatinine. Abnormalities in calcium and phospho rus homeostasis are common, and electrolytes and renal function must be monitored carefully during treatment. Cidofovir Cidofovir is an acyclic nucleotide analog that requires phosphorylation to its active form, cidofovir diphosphate, to exert its antiviral effect. Analogous to penciclovir, it has an extended intracellular half life that contributes to its prolonged antiviral activity. Cidofovir is active against HSV, VZV, and CMV. In contrast to most of the other agents with activ ity against herpesviruses, cidofovir also exhibits broad spectrum activ ity against other DNA viruses, most notably the poxviruses. Cidofovir has activity against the BK virus, a polyomavirus, and therapy may be warranted in some settings of BK reactivation after HSCT and SOT. Cidofovir is useful in the management of adenovirus infections in the immunocompromised host. Cidofovir is also useful in the manage |
7,655 | ment of CMV disease caused by strains with documented ganciclovir resistance. Cidofovir is administered intravenously and is cleared renally by tubular secretion. Extensive prehydration and co administration of probenecid are recommended. Nephrotoxicity is commonly encountered, even with appropriate prehydration; cidofovir must be co administered with care with other nephrotoxic medica tions. Other potential toxicities include reproductive toxicity and carcinogenesis. Trifluridine Trifluridine is a pyrimidine nucleoside analog with activity against HSV, CMV, and adenovirus. It is formulated as a 1 ophthalmic solu tion and approved for topical use in the treatment of HSV keratitis and keratoconjunctivitis. Trifluridine is the treatment of choice for HSV keratitis, a disease that should always be managed in consultation with an ophthalmologist. Vidarabine Vidarabine is a nucleoside analog that has activity against HSV. It was the first parenteral antiviral agent for HSV infection, although it is no longer available for intravenous administration. A topical preparation remains available to treat HSV keratitis and is considered a second line agent for this indication. Fomivirsen Fomivirsen is an anti CMV compound that was used as a second line agent for CMV retinitis by direct injection into the vitreous space. It is an antisense 21 mer DNA oligonucleotide that binds directly to complementary messenger RNA. This agent is of inter est because it was the first antisense antiviral agent approved by the U.S. Food and Drug Administration (FDA). The drug is no longer marketed. Letermovir Letermovir is a highly orally bioavailable agent with a novel mechanism of antiviral action, functioning through interference with the viral ter minase complex. This agent demonstrates substantial promise as an alternative to more toxic antivirals in patients at high risk for CMV disease, particularly in the transplantation setting. It is licensed for prophylaxis for CMV infection and disease in adult CMV seropositive recipients of allogeneic HSCT. Maribavir Maribavir is a licensed orally bioavailable agent that targets the CMV gene product UL97, in the process blocking viral replication. The drug is indicated to treat patients 12 years of age who weigh 35 kg and have evidence of posttransplant CMV infection andor disease that does not respond to other antiviral agents. ANTIVIRALS USED FOR RESPIRATORY VIRAL INFECTIONS Antiviral therapies are available for many respiratory pathogens, including respiratory syncytial virus (RSV), influenza A, and influenza B. Antiviral therapy for respiratory viral infections is of particular value for infants, children with chronic lung disease, and immunocompro mised children. Ribavirin Ribavirin is a guanosine analog that has broad spectrum activ ity against a variety of viruses, particularly RNA viruses. Its precise mechanism of action is incompletely understood but is probably related to interference with viral messenger RNA processing and translation. Ribavirin is available in oral, parenteral, and aerosolized formulations. Although intravenous ribavirin is highly effective in Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1956 Part XV u Infectious Diseases the management of Lassa |
7,656 | fever and other hemorrhagic fevers, this formulation is not licensed for use in the United States. The only licensed formulations in the United States are an aqueous formula tion for aerosol administration (indicated for RSV infection) and an oral formulation that is combined with IFN for the treatment of hepatitis C. (For more information about antivirals for hepatitis, see Chapter 406.) Administration of ribavirin by aerosol should be considered for serious RSV lower respiratory tract disease in immu nocompromised children, young infants with serious RSV associated illness, and high risk infants and children (children with chronic lung disease or cyanotic congenital heart disease). In vitro testing and uncontrolled clinical studies also suggest efficacy of aerosolized ribavirin for parainfluenza, influenza, and measles infections. Ribavirin is generally nontoxic, particularly when administered by aerosol. Oral ribavirin is used in combination with other agents for therapy of hepatitis C (discussed later). There is no role for the use of oral ribavirin in the treatment of community acquired viral respira tory tract infections. Ribavirin and its metabolites concentrate in red blood cells and can persist for several weeks and, in rare instances, may be associated with anemia. Conjunctivitis and bronchospasm have been reported after exposure to aerosolized drug. Care must be taken when using aerosolized ribavirin in children undergoing mechanical ventilation to avoid precipitation of particles in ventilator tubing; the drug is not formally approved for use in the mechani cally ventilated patient, although there is published experience with this approach, which can be considered for mechanically ventilated patients, particularly in a high dose, short duration regimen (6 g100 mL water given for a period of 2 hours 3 times a day). Con cerns regarding potential teratogenicity from animal studies have not been borne out in clinical practice, although care should be taken to prevent inadvertent exposure to aerosolized drug in pregnant health care providers. Amantadine and Rimantadine Amantadine and rimantadine are tricyclic amines (adamantanes) that share structural similarity. Both were indicated for prophylaxis and therapy of influenza A. The mechanism of action of the tricy clic amines against influenza A virus was unclear, but they appeared to exert their antiviral effect at the level of uncoating of the virus. Both agents are extremely well absorbed after oral administration and are eliminated via the kidneys (90 of the dose is unchanged), necessitating dosage adjustments for renal insufficiency. The tox icities of the tricyclic amines are modest and include CNS adverse effects such as anxiety, difficulty concentrating, and lightheaded ness and gastrointestinal adverse effects such as nausea and loss of appetite. Although these agents are still manufactured and available, the Cen ters for Disease Control and Prevention (CDC) no longer recommends the use of the adamantane agents in treatment or prophylaxis against influenza, because of the emergence of widespread resistance. Oseltamivir, Peramivir, Zanamivir (Neuraminidase Inhibitors) These agents are active against both influenza A and B, although the importance of this broader spectrum of antiinfluenza activity in dis ease control is modest because influenza B infection is |
7,657 | typically a much milder illness. Emerging strains of influenza, including H5N1 and the 2009 to 2010 pandemic strain, H1N1 (swine flu), are sus ceptible to oseltamivir and zanamivir but resistant to amantadine. Therefore these agents have emerged as the antivirals of choice for influenza infection. These agents have no appreciable activity against other respiratory viruses. The mechanism of antiviral activity of osel tamivir, zanamivir, and peramivir is via inhibition of the influenza neuraminidase. Unfortunately, oseltamivir resistance may occur as a result of a mutation in 2009 H1N1 viruses, resulting in treatment failure. Zanamivir has poor oral bioavailability and is licensed only for inha lational administration. With inhaled administration, 75 of the dose is deposited in the oropharynx and much of it is swallowed. The actual amount distributed to the airways and lungs depends on factors such as the patients inspiratory flow. Approximately 13 of the dose appears to be distributed to the airways and lungs, with approximately 10 of the inhaled dose distributed systemically. Local respiratory mucosal drug concentrations greatly exceed the drug concentration needed to inhibit influenza A and B viruses. Elimination is via the kidneys, and no dosage adjustment is necessary with renal insufficiency, because the amount systemically absorbed is low. Oseltamivir is administered as an esterified prodrug that has high oral bioavailability. It is eliminated by tubular secretion, and dosage adjustment is required for patients with renal insufficiency. Gastroin testinal adverse effects, including nausea and vomiting, are occasionally observed. The drug is indicated for both treatment and prophylaxis. The usual adult dosage for treatment of influenza is 75 mg twice daily for 5 days. Treatment should be initiated within 2 days of the appear ance of symptoms. Recommended treatment dosages for children vary by age and weight. The recommended dose for children younger than 1 year of age is 3 mgkgdose twice a day. For children older than 1 year of age, doses are 30 mg twice a day for children weighing 15 kg, 45 mg twice a day for children weighing 15 23 kg, 60 mg twice a day for those weighing 23 40 kg, and 75 mg twice a day for chil dren weighing 40 kg. Dosages for chemoprophylaxis are the same for each weight group in children older than 1 year, but the drug should be administered only once daily rather than twice daily. Oseltamivir is FDA approved for therapy of influenza A and B treatment in chil dren 2 weeks of age and older, whereas zanamivir is recommended for treatment of children 7 years of age and older. Current treatment and dosage recommendations for treatment of influenza in children and for chemoprophylaxis are available at https:www.cdc.govfluhighri skchildren antiviral.htm. Oseltamivir has been described to produce neuropsychiatric (narcolepsy) and psychologic (suicidal events) side effects in some patient populations; the drug should be discontinued if behavioral or psychiatric side effects are observed. In late 2014 the FDA approved the neuraminidase inhibitor peramivir for treatment of influenza in pediatrics. It is available as a single dose, intravenous |
7,658 | option. The drug is currently approved for use in children 2 years. The dose is 12 mgkg dose, up to 600 mg maximum, by intravenous infusion for a minimum of 15 minutes in children from 2 to 12 years. Children 13 and older should receive the adult dose (600 mg IV in a single, one time dose). Baloxavir Baloxavir is dosed as baloxavir marboxil, a prodrug that is converted by hydrolysis to baloxavir, the active agent. It is active against influenza A and B. Baloxavir inhibits the endonuclease activity of the influenza polymerase acidic (PA) protein, in the process inhibiting virus replica tion. It is administered as a single dose of 40 mg in individuals 40 80 kg, and 80 mg in those 80 kg. Oral baloxavir marboxil (Xofluza) is approved by the FDA for treat ment of acute uncomplicated influenza within 2 days of illness onset in people 12 years. The safety and efficacy of baloxavir for the treatment of influenza have been established in pediatric patients 12 years and older weighing at least 40 kg. Safety and efficacy in patients 12 years or weighing less than 40 kg have not been established. Baloxavir efficacy is based on clinical trials in outpatients 12 to 64 years of age; people with underlying medical conditions and adults 65 years were not included in the initial published clinical trials. There are no available data for baloxavir treatment of hospitalized patients with influenza. ANTIVIRALS USED FOR COVID 19 The advent of the COVID 19 pandemic has necessitated the urgent development of antivirals active against the SARS CoV 2 virus. Remde sivir is an adenosine analog that was originally developed as a therapeutic option for Ebola virus. It is metabolized to its active metabolite, rem desivir triphosphate, which is a structural analog of adenosine triphos phate and results in delayed chain termination during viral replication. It reduces early stage COVID 19 mortality and the need for mechanical Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 292 u Principles of Antiviral Therapy 1957 ventilation among hospitalized COVID 19 patients. The dose for pediat ric patients less than 12 years of age and weighing at least 3 kg (and 40 kg) is a single loading dose of 5 mgkg on day 1 followed by 2.5 mgkg once daily for up to 5 days; for hospitalized patients requiring invasive mechanical ventilation andor ECMO, up to 10 days total therapy can be administered. Paxlovid (also variably referred to as ritonavir boosted nirmatrelvir) is a therapeutic combination consisting of two compounds: nirmatrelvir, an oral inhibitor of SARS CoV 2 protease, and ritonavir, an inhibitor of the HIV 1 protease. Ritonavir is also a potent inhibitor of cytochrome P 450 (CYP) 3A; thus its inclusion results in higher lev els of PF 07321332. In patients with SARS CoV 2 infection who were treated |
7,659 | with Paxlovid within 3 days of symptom onset, hospitalization and mortality rates were statistically significantly lower compared with placebo. The FDA Emergency Use Authorization (EUA) includes treat ment of children over 12 years of age with a body weight of 40 kg, with a suggested dose of 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet), with all three tablets taken together, twice daily, by oral administration, for 5 days. Molnupiravir (Lagevrio) was originally developed as an influenza antiviral agent. It is a prodrug of a synthetic nucleoside hydroxycytidine derivative. Its antiviral effect is mediated by the introduction of copying errors during the SARS CoV 2 RNA replication cycle. The reported efficacy against hospitalization or death in an adult study of mild or moderate COVID 19 disease was approximately 30. The drug is not authorized for patients 18 years of age because of concerns that it may affect cartilage and bone growth. ANTIVIRALS USED FOR HEPATITIS Seven antiviral agents have been approved by the FDA for treatment of adults with chronic hepatitis B in the United States. These agents are categorized as either IFN 2b and peginterferon 2a) or nucleoside or nucleotide analogs (lamivudine, adefovir, entecavir, tenofovir, tel bivudine). Lamivudine is currently considered the first line therapy in adult patients, but experience in children is limited. In 2012 tenofovir was FDA approved for children with chronic hepatitis B age 12 years weighing 35 kg. Entecavir was approved in the United States for use in children 2 years and older with chronic HBV and evidence of active viral replication and disease activity and, with IFN , is emerging as a first line antiviral regimen for children with hepatitis B who are candi dates for antiviral therapy. Adefovir demonstrates a favorable safety profile and is less likely to select for resistance than lamivudine, but virologic response was limited to adolescent patients and was lower than that of lamivu dine. Most experts recommend watchful waiting of children with chronic hepatitis B infection, because current therapies are only modestly effective at best and evidence of long term benefit is scant. Young children are often thought to be immune tolerant of hepatitis B infection (i.e., they have viral DNA present in serum but normal transaminase levels and no evidence of active hepatitis). These children should have transaminases and viral load moni tored but are not typically considered to be candidates for antiviral therapy. Various formulations of IFNs and ribavirin have been approved by the FDA to treat adults and children with chronic hepatitis C (see Tables 292.1 and 292.2). The impact of hepatitis C genotype had formerly been a major issue in treatment response. Previous studies using ribavirin and pegylated IFNs demonstrated signifi cant genotype dependent differences in responsiveness to antiviral therapy; patients with genotype 1 had the lowest levels of sustained virologic response, and patients with genotype 2 or 3 had the highest response. The development of novel and highly effective antivirals for HCV has revolutionized the care |
7,660 | of hepatitis C patients. Novel drugs include ledipasvir, sofosbuvir, daclatasvir, elbasvir, beclabuvir, grazo previr, paritaprevir, ombitasvir, velpatasvir, and dasabuvir. Ledipas vir, ombitasvir, daclatasvir, elbasvir, and velpatasvir inhibit the virally encoded phosphoprotein NS5A, which is involved in viral replica tion, assembly, and secretion, whereas sofosbuvir is metabolized to a uridine triphosphate mimic, which functions as an RNA chain terminator when incorporated into the nascent RNA by the NS5B polymerase enzyme. Dasabuvir and beclabuvir are also NS5B inhibi tors. Paritaprevir and grazoprevir inhibit the nonstructural protein 3 (NS34) serine protease, a viral nonstructural protein that is the 70 kDa cleavage product of the hepatitis C virus polyprotein. Sofosbuvir in a fixed dose combination was originally licensed for treatment of hepatitis C in adults. It is highly effective (90) for hepa titis C genotypes 1 through 6. In 2020, it was licensed for treatment in children ages 6 years and older and weighing at least 17 kilograms for any of the six HCV genotypes in patients without cirrhosis or with mild cirrhosis. Epclusa in combination with ribavirin is indicated for the treatment of pediatric patients 6 years and older or weighing at least 17 kilograms with severe cirrhosis. ANTIVIRAL IMMUNE GLOBULINS Immune globulins are useful adjuncts in the management of viral dis ease. However, they are most valuable when administered as prophy laxis against infection and disease in high risk patients; their value as therapeutic agents in the setting of established infection is less clear. Varicella zoster immune globulin (human) is valuable for prophy laxis against VZV in high risk children, particularly newborns and immunocompromised children (see Chapter 300). CMV immune globulin is warranted for children at high risk for CMV disease, par ticularly SOT and HSCT patients, and can play a role in preventing injury to the infected fetus when administered to the pregnant patient (see Chapter 302). Palivizumab, a monoclonal antibody with anti RSV activity, is effective for preventing severe RSV lower respiratory tract disease in high risk premature infants and has replaced RSV immune globulin (see Chapter 307). Hepatitis B immune globulin is indicated in infants born to hepatitis B surface antigenpositive mothers (see Chapter 406). A variety of monoclonal antibodies had received FDA EUA clearance for prophylaxis andor therapy of SARS CoV 2 infec tion, including bamlanivimab (LY CoV555; administered alone or in combination with etesevimab), the combination of casirivimab and imdevimab (REGEN COV), and the combination of tixagevimab (AZD8895) and cilgavimab (AZD1061), also known as Evusheld. As of late 2023, these products are no longer available due to their lack of effectiveness against emerging circulating variants of the SARSCoV2 virus. The US Centers for Disease Control and Preventions (CDC) Advisory Committee on Immunization Practices has also recently recommended the routine use of nirsevimab, a monoclonal antibody targeting the prefusion conformation of the RSV F protein, for the prevention of RSV lower respiratory tract disease (see Chapter 307). Treatment is recommended for newborns and infants younger than 8 months of age during, or entering, their first RSV season, as |
7,661 | well as for children up to 24 months of age at increased risk of developing RSV disease entering their second RSV season. A single dose of 50 mg administered intramuscularly is recommended for infants 5 kg, and 100 mg is recommended for infants 5 kg. Nirsevimab should not be given to children 8 months and older who are not at increased risk of severe RSV disease. For the 202324 respiratory virus season, and in light of shortage and distribution issues with nirsevimab, the CDC has recommended (https:emergency.cdc.govhan2023han00499.asp) assigning the highest priority for nirsevimab 100 mg doses for infants at the highest risk for severe RSV disease: young infants (age 6 months and 5 kg) and infants with underlying conditions that place them at highest risk for severe RSV disease. The CDC also recommended that providers not use nirsevimab in palivizumabeligible children ages 819 months for the 202324 RSV season; instead, they should receive palivizumab per American Academy of Pediatrics (AAP) rec ommendations https:publications.aap.orgpediatricsarticle1521 e2023061803192153PalivizumabProphylaxisinInfantsandYoung ?autologincheckredirected). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1958 Part XV u Infectious Diseases Measles is highly contagious, but endemic transmission has been interrupted in the United States as a result of widespread vaccina tion; imported cases have resulted in epidemics in the United States in unimmunized or partially immunized individuals. In some areas of the world, measles remains a major cause of morbidity and mortality in children (Fig. 293.1). ETIOLOGY Measles virus is a negative sense single stranded, lipid enveloped RNA virus in the family Paramyxoviridae and genus Morbillivirus. Other members of the genus Morbillivirus affect a variety of mammals, such as rinderpest virus in cattle and distemper virus in dogs, but humans are the only host of measles virus. Of the six major structural proteins of measles virus, the two most important in terms of induction of immu nity are the hemagglutinin (H) protein and the fusion (F) protein. The neutralizing antibodies are directed against the H protein, and anti bodies to the F protein limit proliferation of the virus during infection. Small variations in genetic composition have also been identified that result in no effect on protective immunity but provide molecular mark ers that can distinguish between viral types. Related genotypes have been grouped by clades, and the World Health Organization (WHO) recognizes 8 clades, A H, and 23 genotypes. These markers have been useful in the evaluation of endemic and epidemic spread of measles. EPIDEMIOLOGY The measles vaccine has changed the epidemiology of measles dra matically. Once worldwide in distribution, endemic transmission of measles has been interrupted in many countries where there is wide spread vaccine coverage. Historically, measles caused universal infec tion in childhood in the United States, with 90 of children acquiring the infection before 15 years of age. Morbidity and mortality associ ated with measles |
7,662 | decreased before the introduction of the vaccine as a result of improvements in healthcare and nutrition. However, the inci dence declined dramatically following the introduction of the measles vaccine in 1963. The attack rate fell from 313 cases per 100,000 popula tion in 19561960 to 1.3 cases per 100,000 in 19821988. A nationwide indigenous measles outbreak occurred in the United States in 19891991, resulting in more than 55,000 cases, 11,000 hos pitalizations, and 123 deaths, demonstrating that the infection had not yet been controlled. This resurgence was attributed to vaccine failure in a small number of school age children, low coverage of preschool age children, and more rapid waning of maternal antibodies in infants born to mothers who had never experienced wild type measles infec tion. Implementation of the two dose vaccine policy and more inten sive immunization strategies resulted in interruption of endemic transmission, and in 2000 measles was declared eliminated from the United States. Measles continues to be imported into the United States; therefore continued maintenance of 90 immunity through vaccination is necessary to prevent widespread outbreaks from occurring (see Fig. 293.1). Since elimination in 2000, there have been several measles epidem ics, with the two largest occurring in 2014 with 667 cases and in 2019 with 1,282 cases. In 2014 there were 23 outbreaks reported, compared with a median of 4 outbreaks reported annually during 20012010. The majority of cases were associated with importations from other countries (returning tourists, adoptees, refugees), particularly from the Philippines, with prior year epidemics associated with epidemics in the WHO European Region. Measles cases were largely restricted to unvaccinated individuals. The epidemic in 2019 resulted in the highest number of cases since 1992, with 89 of cases in unvaccinated or unknown vaccination status, and 10 of cases requiring hospitaliza tion. There were 22 outbreaks in 17 states (7 were multistate outbreaks), and 85 of cases were in close knit, isolated communities where stan dard control measures that generally quickly contain outbreaks were difficult to implement. Population levels of measles immunity of 95 are required to inter rupt the endemic spread of measles. In the United States this can be achieved through the current two dose immunization strategies when coverage rates are high (90 one dose coverage at 12 15 months and 95 two dose coverage in school age children). Although measles mumps rubella coverage remains high (95 for 20112020), pockets of lower coverage rates exist because of reluctance of parents to vac cinate their children. This variability in vaccination has contributed to outbreaks among children in recent years. TRANSMISSION The portal of entry of measles virus is through the respiratory tract or conjunctivae following contact with large droplets or small droplet aerosols in which the virus is suspended. Individuals are infectious from 3 days before to up to 4 6 days after the onset of rash. Approxi mately 90 of exposed susceptible individuals experience measles. Face to face contact is not necessary, because viable virus may be sus pended in air for |
7,663 | as long as 2 hours after the source case leaves a room. Secondary cases from spread of aerosolized virus have been reported in airplanes, physicians offices, and hospitals. PATHOLOGY Measles infection causes necrosis of the respiratory tract epithelium and an accompanying lymphocytic infiltrate. Measles produces a small vessel vasculitis on the skin and on the oral mucous membranes. Histology of the rash and exanthem reveals intracellular edema and dyskeratosis associated with formation of epidermal syncytial giant cells with up to 26 nuclei. Viral particles have been identified within these giant cells. In lymphoreticular tissue, lymphoid hyperplasia is prominent. Fusion of infected cells results in multinucleated giant cells, the Warthin Finkeldey giant cells that are pathognomonic for measles, with up to 100 nuclei and intracytoplasmic and intranuclear inclusions. PATHOGENESIS Measles infection consists of four phases: incubation period, prodro mal illness, exanthematous phase, and recovery. During incubation, measles virus migrates to regional lymph nodes. A primary viremia ensues that disseminates the virus to the reticuloendothelial system. A secondary viremia spreads virus to body surfaces. The prodromal ill ness begins after the secondary viremia and is associated with epithelial necrosis and giant cell formation in body tissues. Cells are killed by cell to cell plasma membrane fusion associated with viral replication that occurs in many body tissues, including cells of the central nervous system. Virus shedding begins in the prodromal phase. With onset of the rash, antibody production begins, and viral replication and symp toms begin to subside. Measles virus also infects CD4 T cells, resulting in suppression of the Th1 immune response and a multitude of other immunosuppressive effects. Measles virus attaches to specific cell receptors to infect host cells. Studies in primates show that the initial targets for measles virus are alveolar macrophages, dendritic cells, and lymphocytes. The cell recep tor in these cells appears to be the signaling lymphocyte activating molecule CD150. Subsequently, respiratory epithelial cells become infected by attachment to the PVRL4 receptor (Nectin4), which is expressed on cells in the trachea, oral mucosa, nasopharynx, and lungs. CLINICAL MANIFESTATIONS Measles is a serious infection characterized by high fever, an enanthem, cough, coryza, conjunctivitis, and a prominent exanthem (Fig. 293.2). After an incubation period of 8 12 days, the prodromal phase begins with a mild fever followed by the onset of conjunctivitis with photo phobia, coryza, a prominent cough, and increasing fever. Koplik spots Chapter 293 Measles Hayley A. Gans Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 293 u Measles 1959 represent the enanthem and are the pathognomonic sign of measles, appearing 1 4 days before the onset of the rash (Fig. 293.3). They first appear as discrete red lesions with bluish white spots in the center on the inner aspects of the cheeks at the level of the premolars. They may spread to involve the lips, hard palate, and gingiva. They |
7,664 | also may occur in conjunctival folds and in the vaginal mucosa. Koplik spots have been reported in 5070 of measles cases but probably occur in the great majority. Symptoms increase in intensity for 2 4 days until the first day of the rash. The rash begins on the forehead (around the hairline), behind the ears, and on the upper neck as a red maculopapular eruption. It then spreads downward to the torso and extremities, reaching the palms and soles in up to 50 of cases. The exanthem frequently becomes conflu ent on the face and upper trunk (Fig. 293.4). With the onset of the rash, symptoms begin to subside. The rash fades over about 7 days in the same progression as it evolved, often leaving a fine desquamation of skin in its wake. Of the major symptoms of measles, the cough lasts the longest, often up to 10 days. In more severe cases, generalized lymphadenopathy may be present, with cervi cal and occipital lymph nodes especially prominent. MODIFIED MEASLES INFECTION In individuals with passively acquired antibody, such as infants and recipients of blood products, a subclinical form of measles may occur. The rash may be indistinct, brief, or, rarely, entirely absent. Similarly, some individuals who have been vaccinated may have a rash but few other symptoms after exposure to measles. Persons with modified mea sles are not considered highly contagious. Goal AFR AMR 2015 measles incidence goal EMR EUR SEAR WPR 1000 100 50 10 01 Estimated number of measles deaths 95 upper confidence limit 95 lower confidence limit 0 05 10 15 A nn ua l n um be r of m ea sl es d ea th s (m ill io ns ) 50 (four countries or 2) 5079 (38 countries or 20) 8089 (33 countries or 17) 90 (119 countries or 61) Not available 10000 Global measles incidence by WHO region, 200015 Estimated annual number of global measles deaths, 200015 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 Year 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 Year MCV1 coverage in infants, 2015 M ea sl es in ci de nc e pe r m ill io n po pu la tio n (lo g sc al e) A B C Fig. 293.1 Progress toward achieving global measles milestones for measles vaccine coverage (A), measles incidence (B), and measles mortality (C). A, Milestone 1: increase routine coverage with the first dose of measles containing vaccine (MCV1) for children age 1 yr to 90 nationally and 80 in every district. Progress: The number of countries with 90 MCV1 coverage increased from 84 (44) in 2000 to 119 (61) in 2015. Among countries with 90 MCV1 coverage nationally, the percentage with |
7,665 | 80 coverage in every district was only 39 of 119 countries in 2015. B, Mile stone 2: reduce global measles incidence to 5 cases1 million population. Progress: reported global annual measles incidence decreased 75 from 2000 to 2015, but only the Region of the Americas achieved the milestone of 5 cases1 million population. C, Milestone 3: reduce global measles mortality by 95 from the 2000 estimate. Progress: the number of estimated global annual measles deaths decreased 79 from 2000 to 2015. AFR, African Region; AMR, Region of the Americas; EMR, Eastern Mediterranean Region; EUR, European Region; SEAR, South East Asia Region; WPR, Western Pacific Region. (From Moss WJ. Measles. Lancet. 2017;390:24902502. Fig. 2; with data from Patel MK, Gacic Dobo M, Strebel PM, et al. Progress toward regional measles eliminationworldwide, 20002015. MMWR Morb Mortal Wkly Rep. 2016;65:12281233.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1960 Part XV u Infectious Diseases LABORATORY FINDINGS The diagnosis of measles is almost always based on clinical and epidemi ologic findings. Laboratory findings in the acute phase include reduction in the total white blood cell count, with lymphocytes decreased more than neutrophils. However, absolute neutropenia has been known to occur. In measles not complicated by bacterial infection, the erythrocyte sedimentation rate and C reactive protein level are usually normal. DIAGNOSIS Isolation of measles from blood, urine, or respiratory secretions can be accomplished by culture at the CDC or local or state laboratories. Molecular detection by polymerase chain reaction (PCR) can be per formed on specimens from nasopharyngeal aspirates, throat swabs, or urine. Serologic confirmation is most conveniently made by identifi cation of immunoglobulin (Ig) M antibody in serum. IgM antibody appears 1 2 days after the onset of the rash and remains detectable for about 1 month. If a serum specimen is collected 72 hours after onset of rash and is negative for measles antibody, a second specimen should be obtained. Serologic confirmation may also be made by dem onstration of a fourfold rise in IgG antibodies in acute and convales cent specimens collected 2 4 weeks apart. Collection of both a throat swab specimen for PCR and a serum specimen for IgM detection is recommended from all patients with clinical features compatible with measles. In addition, samples should be sent to local state public health laboratories or the CDC for genotyping. DIFFERENTIAL DIAGNOSIS Typical measles is unlikely to be confused with other illnesses, espe cially if Koplik spots are observed. Measles in the later stages or modified or atypical infections may be confused with a number of other exanthematous immune mediated illnesses and infections, including rubella, adenovirus infection, enterovirus infection, and Epstein Barr virus infection. Exanthem subitum (in infants) and erythema infectiosum (in older children) may also be confused with measles. Mycoplasma pneumoniae and group A Streptococcus may also produce rashes similar to that of measles. Kawasaki |
7,666 | syndrome can cause many of the same findings as measles but lacks discrete intraoral lesions (Koplik spots) and a severe prodromal cough and typically leads to elevations of neutrophils and acute phase reactants. In addition, the characteristic thrombocytosis of Kawasaki syndrome is absent in measles (see Chapter 208). Drug eruptions may occasion ally be mistaken for measles. Fig. 293.2 Measles disease course (A) and complica tions (B). ADEM, Acute demyelinating encephalomyeli tis; MIBE, measles inclusion body encephalitis; SSPE, subacute sclerosing panencephalitis. (Modified from Moss WJ. Measles. Lancet. 2017;390:24902502. Fig. 4.) 40 39 38 Te m pe ra tu re ( C ) 37 Fever Rash Kopliks spots Conjunctivitis Coryza Cough Disease course 1 2 3 4 5 6 7 8 9 10 Incubation phase Prodromal phase Convalescent phase Rash phase Neurological: ADEM, MIBE, SSPE Pneumonia Otitis media Adverse pregnancy outcomes Complications Keratoconjunctivitis (blindness) Stomatitis Laryngitis (croup) Diarrhea Death A B Fig. 293.3 Koplik spots on the buccal mucosa during the third day of rash. (From Centers for Disease Control and Prevention CDC. Public health image library, image 4500. https:phil.cdc.govDetails.aspx?p id4500.) Fig. 293.4 A child with measles displaying the characteristic red blotchy pattern on his face and body. (From Kremer JR, Muller CP. Measles in Eu ropethere is room for improvement. Lancet. 2009;373:356358.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 293 u Measles 1961 COMPLICATIONS Complications of measles are largely attributable to the pathogenic effects of the virus on the respiratory tract and immune system (Table 293.1, see Fig. 293.2). Several factors make complications more likely. Morbidity and mortality from measles are greatest in individuals younger than 5 years of age (especially 1 year of age) and older than 20 years of age. In resource poor countries, higher case fatality rates have been associated with crowding, possibly attributable to larger inoculum doses after household exposure. Severe malnutrition in children results in a suboptimal immune response and higher mor bidity and mortality with measles infection. Low serum retinol levels in children with measles are associated with higher measles morbid ity and mortality in developing countries and in the United States. Measles infection lowers serum retinol concentrations, so subclinical cases of hyporetinolemia may be made symptomatic during measles. Measles infection in immunocompromised persons is associated with increased morbidity and mortality. Among patients with malig nancy in whom measles develops, pneumonitis occurs in 58 and encephalitis occurs in 20. Pneumonia is the most common cause of death in measles. It may manifest as giant cell pneumonia caused directly by the viral infection or as superimposed bacterial infection. The most common bacterial pathogens are Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. Following severe measles pneumonia, the final common pathway to a fatal outcome is often the development of bron chiolitis obliterans. Croup, tracheitis, and bronchiolitis are common complications in infants and toddlers with measles. The clinical severity |
7,667 | of these com plications frequently requires intubation and ventilatory support until the infection resolves. Acute otitis media is the most common complication of measles and was of particularly high incidence during the epidemic of the late 1980s and early 1990s because of the relatively young age of affected children. Sinusitis and mastoiditis also occur as complications. Viral andor bac terial tracheitis is seen and can be life threatening. Retropharyngeal abscess has also been reported. Measles infection is known to suppress skin test responsiveness to purified tuberculin antigen. There may be a higher rate of activation of pulmonary tuberculosis in populations of individuals infected with Mycobacterium tuberculosis who are then exposed to measles. Diarrhea and vomiting are common symptoms associated with acute measles, and diffuse giant cell formation is found in the epithelium in the gastrointestinal tract. Dehydration is a common consequence, especially in young infants and children. Appendicitis or abdominal pain may occur from obstruction of the appendiceal lumen by lym phoid hyperplasia. Febrile seizures occur in 3 of children with measles. Encepha litis following measles is a long associated complication, often with an unfavorable outcome. Rates of 1 3 in 1,000 cases of measles have been reported, with greater numbers occurring in adolescents and adults than in preschool or school age children. Encephalitis is a postinfectious, immunologically mediated process and is not the result of a direct effect by the virus. Clinical onset begins dur ing the exanthem and manifests as seizures (56), lethargy (46), coma (28), and irritability (26). Findings in cerebrospinal fluid include lymphocytic pleocytosis in 85 of cases and elevated pro tein concentrations. Approximately 15 of patients with measles encephalitis die. Another 2040 of patients suffer long term sequelae, including cognitive impairment, motor disabilities, and deafness. Measles encephalitis in immunocompromised patients results from direct damage to the brain by the virus. Subacute measles encephalitis manifests 1 10 months after measles in immunocompromised patients, particularly those with AIDS, lymphoreticular malignancies, and immunosuppressive therapy. Signs and symptoms include seizures, myoclonus, stupor, and coma. In addition to intracellular inclusions, abundant viral nucleocapsids and viral antigen are seen in brain tis sue. Progressive disease and death almost always occur. A severe form of encephalitis called measles inclusion body encephalitis (MIBE) is being increasingly recognized in immunocompromised hosts, typi cally occurring within a year of infection or vaccination and almost universally resulting in death. Although the pathophysiology is incom pletely understood, the measles viruses implicated in MIBE are usually replication defective, with their genomes possessing numerous muta tions. Diagnosis is confirmed by detection of virus via immunohisto chemistry of brain tissue. A severe form of measles rarely seen nowadays is hemorrhagic mea sles or black measles. It manifested as a hemorrhagic skin eruption and was often fatal. Keratitis, appearing as multiple punctate epithelial foci, resolved with recovery from the infection. Myocarditis is a rare complication of measles. Miscellaneous bacte rial infections have been reported, including bacteremia, cellulitis, and toxic shock syndrome. Measles during pregnancy is associated with high rates of maternal |
7,668 | morbidity, fetal wastage, and stillbirths, with congenital malformations in 3 of liveborn infants. Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis (SSPE) is a chronic complica tion of measles with a delayed onset and an outcome that is nearly always fatal. It appears to result from a persistent infection with an altered measles virus that is harbored intracellularly in the central nervous system for several years. After 7 10 years the virus appar ently regains virulence and attacks the cells in the central nervous system that offered the virus protection. This slow virus infection results in inflammation and cell death, leading to an inexorable neu rodegenerative process. TABLE 293.1 Complications by Age for Reported Measles Cases, United States, 19872000 COMPLICATION OVERALL (67,032 CASES WITH AGE INFORMATION) NO. () OF PERSONS WITH COMPLICATION BY AGE GROUP 5 YR (N 28,730) 5 9 YR (N 6,492) 10 19 YR (N 18,580) 20 29 YR (N 9,161) 30 YR (N 4,069) Any 19,480 (29.1) 11,883 (41.4) 1,173 (18.1) 2,369 (12.8) 2,656 (29.0) 1,399 (34.4) Death 177 (0.3) 97 (0.3) 9 (0.1) 18 (0.1) 26 (0.3) 27 (0.7) Diarrhea 5,482 (8.2) 3,294 (11.5) 408 (6.3) 627 (3.4) 767 (8.4) 386 (9.5) Encephalitis 97 (0.1) 43 (0.2) 9 (0.1) 13 (0.1) 21 (0.2) 11 (0.3) Hospitalization 12,876 (19.2) 7,470 (26.0) 612 (9.4) 1,612 (8.7) 2,075 (22.7) 1,107 (27.2) Otitis media 4,879 (7.3) 4,009 (14.0) 305 (4.7) 338 (1.8) 157 (1.7) 70 (1.7) Pneumonia 3,959 (5.9) 2,480 (8.6) 183 (2.8) 363 (2.0) 554 (6.1) 379 (9.3) From Perry RT, Halsey NA. The clinical significance of measles: a review. Clin Infect Dis. 2004;189(Suppl. 1):S4S16. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1962 Part XV u Infectious Diseases SSPE is a rare disease and generally follows the prevalence of measles in a population. The incidence in the United States in 1960 was 0.61 cases per million persons younger than age 20 years. By 1980 the rate had fallen to 0.06 cases per million. Between 1956 and 1982 a total of 634 cases of SSPE had been reported to the national SSPE registry. After 1982 5 casesyear were reported annually in the United States, and only 2 3 casesyear were reported in the early 1990s. However, between 1995 and 2000, reported cases in the United States increased and 13 cases were reported in 2000. Of the 13 cases, 9 occurred in foreign born individuals. This resurgence may be the result of an increased incidence of measles between 1989 and 1991. Although the age of onset ranges from 1 year to 30 years, the illness is primarily one of chil dren and adolescents. Measles at an early age favors the development of SSPE: 50 of patients with SSPE have had primary measles before 2 years of age, and 75 have had measles before 4 years of age. Males are affected twice as often as females, |
7,669 | and there appear to be more cases reported from rural than urban populations. Recent observations from the registry indicate a higher prevalence among children of Hispanic origin. The pathogenesis of SSPE remains enigmatic. Factors that seem to be involved include defective measles virus and interaction with a defec tive or immature immune system. The virus isolated from brain tissue of patients with SSPE is missing one of the six structural proteins, the matrix or M protein. This protein is responsible for assembly, orien tation, and alignment of the virus in preparation for budding during viral replication. Immature virus may be able to reside, and possibly propagate, within neuronal cells for long periods. The fact that most patients with SSPE were exposed at a young age suggests that immune immaturity is involved in pathogenesis. Clinical manifestations of SSPE begin insidiously 7 13 years after primary measles infection. Subtle changes in behavior or school performance appear, including irritability, reduced attention span, and temper outbursts. This initial phase (stage I) may at times be missed because of brevity or mildness of the symptoms. Fever, head ache, and other signs of encephalitis are absent. The hallmark of the second stage is massive myoclonus, which coincides with extension of the inflammatory process site to deeper structures in the brain, including the basal ganglia. Involuntary movements and repetitive myoclonic jerks begin in single muscle groups but give way to mas sive spasms and jerks involving both axial and appendicular mus cles. Consciousness is maintained. In the third stage, involuntary movements disappear and are replaced by choreoathetosis, immo bility, dystonia, and lead pipe rigidity that result from destruction of deeper centers in the basal ganglia. The sensorium deteriorates into dementia, stupor, and then coma. The fourth stage is charac terized by loss of critical centers that support breathing, heart rate, and blood pressure. Death soon ensues. Progression through the clinical stages may follow courses characterized as acute, subacute, or chronic progressive. The diagnosis of SSPE can be established through documenta tion of a compatible clinical course and at least one of the following supporting findings: (1) measles antibody detected in cerebro spinal fluid, (2) characteristic electroencephalographic findings, and (3) typical histologic findings in andor isolation of virus or viral antigen from brain tissue obtained by biopsy or postmortem examination. Cerebrospinal fluid analysis reveals normal cells but elevated IgG and IgM antibody titers in dilutions 1:8. Electroencephalographic patterns are normal in stage I, but in the myoclonic phase, suppression burst episodes are seen that are characteristic of, but not pathognomonic for, SSPE. Brain biopsy is no longer routinely indicated for diagnosis of SSPE. Management of SSPE is primarily supportive and similar to care provided to patients with other neurodegenerative diseases. Clinical trials using isoprinosine with or without interferon suggest significant benefit (3034 remission rate) compared with patients without treat ment (510 with spontaneous remissions). It is recognized that carbamazepine is of significant benefit in the control of myoclonic jerks in the early stages of the illness. Virtually all |
7,670 | patients eventually succumb to SSPE. Most die within 1 3 years of onset from infection or loss of autonomic control mecha nisms. Prevention of SSPE depends on prevention of primary measles infection through vaccination. SSPE has been described in patients who have no history of measles infection and exposure only to the vac cine virus. However, wild type virus, not vaccine virus, has been found in brain tissue of at least some of these patients, suggesting that they had subclinical measles previously. TREATMENT Management of measles is supportive because there is no specific antiviral therapy approved for treatment of measles. Maintenance of hydration, oxygenation, and comfort are goals of therapy. Antipyret ics for comfort and fever control are useful. For patients with respi ratory tract involvement, airway humidification and supplemental oxygen may be of benefit. Respiratory failure from croup or pneumo nia may require ventilatory support. Oral rehydration is effective in most cases, but severe dehydration may require intravenous therapy. Prophylactic antimicrobial therapy to prevent bacterial infection is not indicated. Measles infection in immunocompromised patients is highly lethal. Ribavirin is active in vitro against measles virus. Anecdotal reports of ribavirin therapy with or without intravenous gamma globulin sug gest some benefit in individual patients. Although no controlled trials have been performed, many experts favor use of ribavirin for treat ment of measles pneumonia in patients 12 months, patients 12 months with pneumonia requiring ventilatory support, and patients with severe immunosuppression. Ribavirin dosing is 15 20 mgkg day orally in two divided doses. The optimal duration of therapy is not known; a duration of 5 7 days may be reasonable, guided by the patients clinical status (respiratory symptoms and chest radiograph findings). Several investigational treatments have been used in indi viduals with SSPE with the goal of stabilization and delay of progres sion, including Isoprinosine (inosine pranobex) and interferon and interferon . Vitamin A Vitamin A deficiency in children in resource poor countries has long been known to be associated with increased mortality from a variety of infectious diseases, including measles. In the United States, studies in the early 1990s documented that 2272 of children with measles had low retinol levels. In addition, one study demonstrated an inverse correlation between the level of retinol and severity of illness. Several randomized controlled trials of vitamin A therapy in the develop ing world have demonstrated reduced morbidity and mortality from measles. Use of vitamin A for treatment of measles in developed coun tries has not been evaluated in a large clinical trial, but a small study showed no effect on morbidity. Given the potential for benefit, the WHO and the CDC recommend that vitamin A be administered to all children with acute measles, even in countries where measles is not usually severe. Vitamin A should be administered once daily for 2 days at doses of 200,000 IU for children 12 months of age or older; 100,000 IU for infants 6 11 months of age; and 50,000 IU for infants younger than 6 months |
7,671 | of age. In children with signs and symptoms of vitamin A deficiency, a third age appropriate dose is recommended 2 4 weeks after the second dose. PROGNOSIS In the early 20th century, deaths from measles in the United States var ied between 2,000 and 10,000 per year, or about 10 deaths per 1,000 cases of measles. With improvements in healthcare and antimicro bial therapy, better nutrition, and decreased crowding, the death to case ratio fell to 1 per 1,000 cases. Between 1982 and 2002, the CDC estimated that there were 259 deaths caused by measles in the United States, with a death to case ratio of 2.5 2.8 per 1,000 cases of measles. Pneumonia and encephalitis were complications in most of the fatal cases, and immunodeficiency conditions were identified in 1416 of deaths. In 2011, of the 222 cases reported in the United States, 70 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 293 u Measles 1963 (32) were hospitalized, including 17 (24) with diarrhea, 15 (21) with dehydration, and 12 (17) with pneumonia. No cases of encepha litis or deaths were reported. In 2019, 10 of cases were hospitalized, 5 had pneumonia, and one (0.1) had encephalitis, but no deaths were reported. PREVENTION Patients shed measles virus from 7 days after exposure to 4 6 days after the onset of rash. Exposure of susceptible individuals to those with measles should be avoided during this period. In hospitals, stan dard and airborne precautions should be observed for this period. Immunocompromised individuals with measles will shed virus for the duration of the illness, so isolation should be maintained throughout the disease. Vaccine Vaccination against measles is the most effective and safe prevention strategy. Measles vaccine in the United States is available as a com bined vaccine with measles mumps rubella vaccine (Table 293.2). After the measles resurgence of 19891991, a second dose of measles vaccine was added to the schedule. The current recommendations include a first dose at 12 15 months of age and a second dose at 4 6 years of age. However, the second dose can be given any time after 30 days following the first dose, and the current schedule is a con venience schedule. Seroconversion is slightly lower in children who receive the first dose before or at 12 months of age (87 at 9 months, 95 at 12 months, and 98 at 15 months) because of persisting maternal antibody; however, this is an evolving situation, with chil dren currently as young as 6 months unprotected from maternal anti bodies and susceptible to measles infection. For children who have not received two doses by 11 12 years of age, a second dose should be provided. Infants who receive a dose before 12 months of age should be given two additional doses, one at 12 15 months and another at 4 |
7,672 | 6 years of age. Children who are traveling should be offered either primary measles immunization even as young as 6 months or a sec ond dose even if 4 years. Adverse events from the measles mumps rubella vaccine include fever (usually 6 12 days after vaccination), rash in approximately 5 of vaccinated persons, and, rarely, transient thrombocytopenia. Chil dren prone to febrile seizures may experience an event following vac cination, so the risks and benefits of vaccination should be discussed with parents. Encephalopathy and autism have not been shown to be causally associated with the measles mumps rubella vaccine or vac cine constituents. A review of the effect of measles vaccination on the epidemiology of SSPE has demonstrated that measles vaccination protects against SSPE TABLE 293.2 Recommendations for Measles Immunization CATEGORY RECOMMENDATIONS Unimmunized, no history of measles (12 15 mo of age) MMR or MMRV vaccine is recommended at 12 15 mo of age; a second dose is recommended at least 28 days after the first dose (or 90 days for MMRV) and usually is administered at 4 through 6 yr of age Children 6 11 mo of age in epidemic situations or before international travel Immunize with MMR vaccine, but this dose is not considered valid, and 2 valid doses administered on or after the first birthday are required. The first valid dose should be administered at 12 15 mo of age; the second valid dose is recommended at least 28 days later and usually is administered at 4 through 6 yr of age. MMRV should not be administered to children 12 mo of age. Students in kindergarten, elementary, middle, and high school who have received 1 dose of measles vaccine at 12 mo of age or older Administer the second dose Students in college and other postsecondary institutions who have received 1 dose of measles vaccine at 12 mo of age or older Administer the second dose History of immunization before the first birthday Dose not considered valid; immunize (2 doses) CATEGORY RECOMMENDATIONS History of receipt of inactivated measles vaccine or unknown type of vaccine, 19631967 Dose not considered valid; immunize (2 doses) Further attenuated or unknown vaccine administered with immunoglobulin Dose not considered valid; immunize (2 doses) Allergy to eggs Immunize; no reactions likely Neomycin allergy, nonanaphylactic Immunize; no reactions likely Severe hypersensitivity (anaphylaxis) to neomycin or gelatin Avoid immunization Tuberculosis Immunize; if patient has untreated tuberculosis disease, start antituberculosis therapy before immunizing Measles exposure Immunize or give immunoglobulin, depending on circumstances HIV infected Immunize (2 doses) unless severely immunocompromised; administration of immunoglobulin if exposed to measles is based on degree of immunosuppression and measles vaccine history Personal or family history of seizures Immunize; advise parents of slightly increased risk of seizures Immunoglobulin or blood recipient Immunize at the appropriate interval MMR, Measles mumps rubella vaccine; MMRV, measles mumps rubella varicella vaccine. From American Academy of Pediatrics. Measles. In Kimberlin DW, Brady MT, Jackson MA, Long SS, eds. Red Book 2018 Report of the Committee on Infectious |
7,673 | Diseases, 31st ed. Itasca, IL: American Academy of Pediatrics, 2018: Table 3.39, p. 543. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1964 Part XV u Infectious Diseases TABLE 293.3 Suggested Intervals Between Immunoglobulin Administration and Measles Immunization INDICATION FOR IMMUNOGLOBULIN DOSE ROUTE UNITS (U) OR MILLILITERS (ML) MG IgGKG INTERVAL (MO) Tetanus (as tetanus Ig) IM 250 U 10 3 Hepatitis A prophylaxis (as Ig): Contact prophylaxis IM 0.02 mLkg 3.3 3 International travel IM 0.06 mLkg 10 3 Hepatitis B prophylaxis (as hepatitis B Ig) IM 0.06 mLkg 10 3 Rabies prophylaxis (as rabies Ig) IM 20 IUkg 22 4 Varicella prophylaxis (as VariZIG) IM 125 U10 kg (maximum 625 U) 20 40 5 Measles prophylaxis (as Ig): Standard IM 0.50 mLkg 80 6 Immunocompromised host IV 400 mgkg 8 Respiratory syncytial virus prophylaxis (palivizumab monoclonal antibody) IM 15 mgkg (monoclonal) None Cytomegalovirus immune globulin IV 3 mLkg 150 6 Blood transfusion: Washed RBCs IV 10 mLkg Negligible 0 RBCs, adenine saline added IV 10 mLkg 10 3 Packed RBCs IV 10 mLkg 20 60 6 Whole blood IV 10 mLkg 80 100 6 Plasma or platelet products IV 10 mLkg 160 7 Replacement (or therapy) of immune deficiencies (as IVIG) IV 300 400 8 ITP (as IVIG) IV 400 8 ITP IV 1,000 10 ITP or Kawasaki disease IV 1,600 2,000 11 Immunization in the form of measles mumps rubella (MMR), measles mumps rubella varicella (MMRV), or monovalent measles vaccine. These intervals should provide sufficient time for decreases in passive antibodies in all children to allow for an adequate response to measles vaccine. Physicians should not assume that children are fully protected against measles during these intervals. Additional doses of Ig or measles vaccine may be indicated after exposure to measles. Monoclonal antibodies, such as palivizumab, do not interfere with the immune response to vaccines. Ig, Immunoglobulin; IgG, immunoglobulin G; ITP, immune (formerly termed idiopathic) thrombocytopenic purpura; IVIG, intravenous Ig; RBCs, red blood cells. From American Academy of Pediatrics. Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2015: Table 1.10, p. 39. and does not accelerate the course of SSPE or trigger the disease in those already infected with wild measles virus. Passively administered immune globulin may inhibit the immune response to live measles vaccine, and administration should be delayed for variable amounts of time based on the dose of Ig (Table 293.3). Live vaccines should not be administered to pregnant women or to immunodeficient or immunosuppressed patients. However, patients with HIV who are not severely immunocompromised should be immu nized. Because measles virus may suppress the cutaneous response to tuberculosis antigen, skin testing for tuberculosis should be performed before or at the same time as administration of the vaccine. Individuals infected with M. tuberculosis should be receiving appropriate |
7,674 | treatment at the time of administration of measles vaccine. Postexposure Prophylaxis Susceptible individuals exposed to measles may be protected from infection either by vaccine administration or with Ig. The vaccine is effective in prevention or modification of measles if given within 72 hours of exposure. Ig may be given up to 6 days after exposure to pre vent or modify infection. Immunocompetent children should receive 0.5 mLkg (maximum dose in both cases is 15 mLkg) intramuscularly. For severely immunocompromised children and pregnant woman without evidence of measles immunity, immunoglobulin intravenously (IGIV) is the recommended Ig at 400 mgkg. Ig is indicated for suscep tible household contacts of patients with measles, especially infants 6 months of age, pregnant women, and immunocompromised persons. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 294 u Rubella 1965 Rubella (German measles or 3 day measles) is a mild, often exan thematous disease of childhood that is typically more severe and asso ciated with more complications in adults. Its major clinical significance is transplacental infection and fetal damage as part of the congenital rubella syndrome (CRS). ETIOLOGY Rubella virus is a member of the family Togaviridae and is the only spe cies of the genus Rubivirus. It is a positive sense single stranded RNA virus with a lipid envelope and three structural proteins, including a nucleocapsid protein (C) that is associated with the nucleus and two glycoproteins, E1 and E2, that are associated with the envelope, carry the main epitopes, and therefore are the major antigenic sites of the virus. The virus is sensitive to heat, ultraviolet light, and extremes of pH but is relatively stable at cold temperatures. Humans are the only known reservoir. EPIDEMIOLOGY Rubella is found worldwide and circulates predominantly in late winter and early spring. In the United States, in the prevaccine era, rubella appeared to occur in major epidemics every 6 9 years, with smaller peaks interspersed every 3 4 years, and was most com mon in preschool age and school age children. During the rubella epidemic of 19641965 there were an estimated 12.5 million cases of rubella associated with 2,000 cases of encephalitis, more than 13,000 abortions or perinatal deaths, and 20,000 cases of CRS. After introduction of the rubella vaccine in 1969 in the United States, the incidence of rubella fell 78 and CRS cases fell 69 by 1976 (Fig. 294.1). Further decline in rubella and CRS cases occurred when certain at risk populations were added to those for whom rubella immunization is indicated, including adolescents and col lege students. After years of decline, a resurgence of rubella and CRS cases occurred during 19891991 in association with the epi demic of measles during that period (see Fig. 294.1). Subsequently, a two dose recommendation for rubella vaccine was implemented and resulted in a decrease in incidence |
7,675 | of rubella from 0.45 per 100,000 population in 1990 to 0.1 per 100,000 population in 1999 and a corresponding decrease of CRS, with an average of six infants with CRS reported annually from 1992 to 2004. Mothers of these infants tended to be young, Hispanic, or foreign born. The number of reported cases of rubella continued to decline through the 1990s and the first decade of this century. The endemic spread of rubella was declared eliminated in the United States in 2004 and eliminated in the Americas in 2015. However, cases of rubella continue to be imported into the United States from coun tries where it remains endemic. Accelerated global vaccine efforts have resulted in declines of rubella cases worldwide from 94,277 in 2012 to 10,194 in 2020. Rubella elimination has been verified in 93 (48) of 194 countries, with 70 of infants globally receiving a rubella vaccine in 2020. From 2004 to 2016 there were 101 cases of rubella and 11 cases of CRS reported in the United States, all of which were imported cases of unknown source. Three of the CRS cases were acquired in Africa. This information highlights the need for continued maintenance of high levels of immunity in the United States. PATHOLOGY Little information is available on the pathologic findings in rubella occurring postnatally. The few reported studies of biopsy or autopsy material from cases of rubella revealed only nonspecific findings of lymphoreticular inflammation and mononuclear perivascular and meningeal infiltration. The pathologic findings for CRS are often severe and may involve nearly every organ system (Table 294.1). PATHOGENESIS The viral mechanisms for cell injury and death in postnatal or congeni tal rubella are not well delineated. The main mechanisms of transmis sion is respiratory for postnatal infection and transplacental in CRS. The incubation period following respiratory exposure averages 14 days, with a range from 12 to 23 days. After infection, the virus replicates in the respiratory epithelium and then spreads to regional lymph nodes (Fig. 294.2). Viremia ensues and is most intense from 10 to 17 days after infection. Viral shedding from the nasopharynx begins approxi mately 10 days after infection and may be detected up to 2 weeks after onset of the rash. The period of highest communicability is from 5 days before to 6 days after the appearance of the rash. Congenital infection occurs during maternal viremia. After infect ing the placenta, the virus spreads through the vascular system of the developing fetus and may infect any fetal organ. The most important risk factor for severe congenital defects is the stage of gestation at the time of infection. Maternal infection during the first 8 weeks of ges tation results in the most severe and widespread defects. The risk for congenital defects has been estimated at 90 for maternal infection before 11 weeks of gestation, 33 at 11 12 weeks, 11 at 13 14 weeks, and 24 at 15 16 weeks. Defects occurring after 16 weeks of gestation are uncommon, even if fetal infection occurs. |
7,676 | Causes of cellular and tissue damage in the infected fetus may include tissue necrosis due to vascular insufficiency, reduced cellular multiplication time, chromosomal breaks, and production of a protein inhibitor causing mitotic arrests in certain cell types. The most distinc tive feature of congenital rubella is chronicity. Once the fetus is infected early in gestation, the virus persists in fetal tissue until well beyond delivery. Persistence suggests the possibility of ongoing tissue damage and reactivation, most notably in the brain. CLINICAL MANIFESTATIONS Postnatal infection with rubella is typically a mild disease not easily discernible from other viral infections, especially in children. After an incubation period of 12 23 days, a prodrome consisting of low grade fever, sore throat, red eyes with or without eye pain, headache, malaise, anorexia, and lymphadenopathy begins. Suboccipital, postauricular, and anterior cervical lymph nodes are most prominent. In children, the first manifestation of rubella is usually the rash, which is vari able and not distinctive, often more prominent with heat. It begins on the face and neck as small, irregular pink macules that coalesce, and it spreads centrifugally to involve the torso and extremities, where Chapter 294 Rubella Hayley A. Gans 70,000 60,000 40,000 50,000 20,000 30,000 10,000 0 1966 1971 1976 1981 1986 19961991 Year N o. r ub el la c as es N o. C R S cases By year of birth. 2001 2011 0 10 20 30 40 50 60 70 80 90 100 Rubella Number of rubella and congenital rubella syndrome (CRS) casesUnited States,19662011 CRS 2006 Fig. 294.1 Number of rubella and congenital rubella syndrome cas esUnited States, 19662011. Rubella and CRS data provided were reported voluntarily to Centers for Disease Control and Prevention from state health departments. (From McLean HQ, Fiebelkorn AP, Temte JL, et al. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013. MMWR Recomm Rep. 2013;62RR 04:134.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1966 Part XV u Infectious Diseases it tends to occur as discrete macules (Fig. 294.3). About the time of onset of the rash, examination of the oropharynx may reveal tiny, rose colored lesions (Forchheimer spots) or petechial hemorrhages on the soft palate. The rash fades from the face as it extends to the rest of the body so that the whole body may not be involved at any one time. The duration of the rash is generally 3 days, and it usually resolves with out desquamation. Subclinical infections are common, and 2540 of children may not have a rash. Teenagers and adults tend to be more symptomatic and have systemic manifestations, with up to 70 of females demonstrating arthralgias and arthritis. LABORATORY FINDINGS Leukopenia, neutropenia, and mild thrombocytopenia have been described during postnatal rubella. DIAGNOSES A specific diagnosis of rubella is important for epidemiologic reasons, for diagnosis of infection in pregnant women, and for confirmation |
7,677 | of the diagnosis of congenital rubella. The most common diagnostic test is rubella immunoglobulin (Ig) M enzyme immunosorbent assay, which is typically present 4 days after the appearance of the rash. As with any serologic test, the positive predictive value of testing decreases in populations with low prevalence of disease and in immunized indi viduals. Tests should be performed in the context of a supportive his tory of exposure or consistent clinical findings. The relative sensitivity and specificity of commercial kits used in most laboratories range from 9699 and 8697, respectively. A caveat for testing of congenitally infected infants early in infancy is that false negative results may occur owing to competing IgG antibodies circulating in these patients. In TABLE 294.1 Pathologic Findings in Congenital Rubella Syndrome SYSTEM PATHOLOGIC FINDINGS Cardiovascular Patent ductus arteriosus Pulmonary artery stenosis Ventriculoseptal defect Myocarditis Central nervous system Chronic meningitis Parenchymal necrosis Vasculitis with calcification Eye Microphthalmia Cataract Iridocyclitis Ciliary body necrosis Glaucoma Retinopathy Ear Cochlear hemorrhage Endothelial necrosis Lung Chronic mononuclear interstitial pneumonitis Liver Hepatic giant cell transformation Fibrosis Lobular disarray Bile stasis Kidney Interstitial nephritis Adrenal gland Cortical cytomegaly Bone Malformed osteoid Poor mineralization of osteoid Thinning cartilage Spleen, lymph node Extramedullary hematopoiesis Thymus Histiocytic reaction Absence of germinal centers Erythropoiesis in dermisSkin Fig. 294.2 Pathophysiologic events in postnatally acquired rubella virus infection. Possible complications in clude arthralgia andor arthritis, throm bocytopenic purpura, and encepha litis. CF, Complement fixation titer; HI, hemagglutination inhibition titer. (From Lamprecht CL. Rubella virus. In: Beshe RB, ed. Textbook of Human Virology, 2nd ed. Littleton, MA: PSG Publishing; 1990:685. )Days Mo Yr 16 14 12 10 8 6 4 2 0 2 4 6 1 2 3 4 1 2 3 45 6 A nt ib od y le ve ls HI NeutralizingFever CF Viral excretion from pharynx Viremia Lymph node enlargement RASH Malaise, sore throat (Complications) Exposure to rubella Incubation 1618 days Illness 14 days Convalescence Fig. 294.3 Rash of rubella. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 294 u Rubella 1967 such patients, an IgM capture assay, reverse transcriptase polymerase chain reaction (PCR) test, or viral culture should be performed for con firmation. Virus can be detected by PCR in nasal, throat, urine, blood, and cerebrospinal fluid (CSF) specimens up to 10 days after rash onset (with highest yield within 3 days). Viral isolation by culture or PCR of nasopharyngeal secretions, urine in the newborn (as close to birth as possible), or cord blood or placenta can be used to diagnose congenital infection. PCR testing of amniotic fluid during pregnancy is also an appropriate approach to diagnose congenital infection. If CRS is con firmed, infants should be screened for viral shedding monthly after the age of 3 months until two consecutive negative tests are obtained. Viral shedding may be detected for up to 1 year. DIFFERENTIAL DIAGNOSES Rubella |
7,678 | may manifest as distinctive features suggesting the diagnosis. It is frequently confused with other infections because it is uncommon, is similar to other viral exanthematous diseases, and demonstrates variability in the presence of typical findings. In severe cases, it may resemble measles. The absence of Koplik spots, a severe prodrome, and a shorter course, allow for differentiation from measles. Other diseases frequently confused with rubella include infections caused by adeno viruses, parvovirus B19 (erythema infectiosum), Epstein Barr virus, enteroviruses, roseola, and Mycoplasma pneumoniae. COMPLICATIONS Complications following postnatal infection with rubella are infre quent and generally not life threatening. Postinfectious thrombocytopenia occurs in approximately 1 in 3,000 cases of rubella and occurs more frequently among children and in girls. It manifests about 2 weeks after the onset of the rash as pete chiae, epistaxis, gastrointestinal bleeding, and hematuria and is usually self limited. Arthritis following rubella occurs more commonly among adults, especially women. It begins within 1 week of onset of the exanthem and classically involves the small joints of the hands. It is self limited and resolves within weeks without sequelae. There are anecdotal reports and some serologic evidence linking rubella with rheumatoid arthritis, but a true causal association remains speculative. Encephalitis is the most serious complication of postnatal rubella. It occurs in two forms: a postinfectious syndrome following acute rubella and a rare progressive panencephalitis manifesting as a neurodegen erative disorder years after rubella. Postinfectious encephalitis is uncommon, occurring in 1 in 5,000 cases of rubella. It appears within 7 days after onset of the rash, consist ing of headache, seizures, confusion, coma, focal neurologic signs, and ataxia. Fever may recrudesce with the onset of neurologic symptoms. CSF may be normal or have a mild mononuclear pleocytosis andor elevated protein concentration. Virus is rarely, if ever, isolated from CSF or brain, suggesting a noninfectious pathogenesis. Most patients recover completely, but mortality rates of 20 and long term neuro logic sequelae have been reported. Progressive rubella panencephalitis (PRP) is an extremely rare complication of either acquired rubella or CRS. It has an onset and course similar to those of the subacute sclerosing panencephalitis asso ciated with measles (see Chapter 293). However, unlike in the postin fectious form of rubella encephalitis, rubella virus may be isolated from brain tissue of the patient with PRP, suggesting an infectious patho genesis, albeit a slow one. The clinical findings and course are indis tinguishable from those of subacute sclerosing panencephalitis and transmissible spongiform encephalopathies (see Chapter 324). Death occurs 2 5 years after onset. Other neurologic syndromes rarely reported with rubella include Guillain Barr syndrome and peripheral neuritis. Myocarditis is a rare complication. Congenital Rubella Syndrome In 1941 an ophthalmologist first described a syndrome of cataracts and congenital heart disease that he correctly associated with rubella infections in the mothers during early pregnancy (Table 294.2). Shortly after the first description, hearing loss was recognized as a common finding often associated with microcephaly. In 1964 to 1965 a pan demic of rubella occurred, with 20,000 |
7,679 | cases reported in the United States, leading to more than 11,000 spontaneous or therapeutic abor tions and 2,100 neonatal deaths. From this experience emerged the expanded definition of CRS that includes numerous other transient or permanent abnormalities. Nerve deafness is the single most common finding among infants with CRS. Most infants have some degree of intrauterine growth restriction. Retinal findings described as salt and pepper retinopathy are the most common ocular abnormality but have little early effect on vision. Unilateral or bilateral cataracts are the most serious eye finding, occurring in about a third of infants (Fig. 294.4). Cardiac abnormalities occur in half of the children infected during the first 8 weeks of gesta tion. Patent ductus arteriosus is the most frequently reported cardiac defect, followed by lesions of the pulmonary arteries and valvular dis ease. Interstitial pneumonitis leading to death in some cases has been reported. Neurologic abnormalities are common and may progress following birth. Meningoencephalitis is present in 1020 of infants with CRS and may persist for up to 12 months. Longitudinal follow up through 9 12 years of infants without initial retardation revealed progressive development of additional sensory, motor, and behavioral abnormalities, including hearing loss and autism. PRP has also been recognized rarely after CRS. Subsequent postnatal growth retardation and ultimate short stature have been reported in a minority of cases. Rare reports of immunologic deficiency syndromes have also been described. A variety of late onset manifestations of CRS have been recognized. In addition to PRP, they include diabetes mellitus (20), thyroid dys function (5), and glaucoma and visual abnormalities associated with the retinopathy, which had previously been considered benign. TREATMENT There is no specific treatment available for either acquired rubella or CRS. TABLE 294.2 Clinical Manifestations of Congenital Rubella Syndrome in 376 Children After Maternal Rubella MANIFESTATION RATE () Deafness 67 Ocular 71 Cataracts 29 Retinopathy 39 Heart disease 48 Patent ductus arteriosus 78 Right pulmonary artery stenosis 70 Left pulmonary artery stenosis 56 Valvular pulmonic stenosis 40 Low birthweight 60 Psychomotor delay 45 Neonatal purpura 23 Death 35 Other findings: hepatitis, linear streaking of bone, hazy cornea, congenital glaucoma, delayed growth. Findings in 87 patients with congenital rubella syndrome and heart disease who underwent cardiac angiography. From Cooper LZ, Ziring PR, Ockerse AB, et al. Rubella: clinical manifestations and management. Am J Dis Child. 1969;118:1829. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1968 Part XV u Infectious Diseases SUPPORTIVE CARE Postnatal rubella is generally a mild illness that requires no care beyond antipyretics and analgesics. Intravenous immunoglobu lin or corticosteroids can be considered for severe, nonremitting thrombocytopenia. Management of children with CRS is more complex and requires pediatric, cardiac, audiologic, ophthalmologic, and neurologic evalu ation and follow up because many manifestations may not be readily apparent initially or may worsen with time. Hearing screening is of special importance |
7,680 | because early intervention may improve outcomes in children with hearing problems caused by CRS. PROGNOSIS Postnatal infection with rubella has an excellent prognosis. Long term outcomes of CRS are less favorable and somewhat variable. In an Aus tralian cohort evaluated 50 years after infection, many had chronic conditions but most were married and had made good social adjust ments. A cohort from New York from the mid 1960s epidemic had less favorable outcomes, with 30 leading normal lives, 30 in depen dent situations but functional, and 30 requiring institutionalization and continuous care. Reinfection with wild virus occurs postnatally in both individu als who were previously infected with wild virus rubella and vacci nated individuals. Reinfection is defined serologically as a significant increase in IgG antibody level andor an IgM response in an individ ual who has a documented preexisting rubella specific IgG above an accepted cutoff. Reinfection may result in an anamnestic IgG response, an IgM and IgG response, or clinical rubella. There are 29 reports in the literature of CRS following maternal reinfection. Reinfection with serious adverse outcomes to adults or children is rare and of unknown significance. PREVENTION Patients with postnatal infection should be isolated from susceptible individuals for 7 days after onset of the rash. Standard plus droplet precautions are recommended for hospitalized patients. Children with CRS may excrete the virus in respiratory secretions up to 1 year of age, so contact precautions should be maintained for them until 1 year of age, unless repeated cultures of urine and pharyngeal secretions are negative. Similar precautions apply to patients with CRS with regard to attendance in school and out of home childcare. Exposure of susceptible pregnant women poses a potential risk to the fetus. For pregnant women exposed to rubella, a blood speci men should be obtained as soon as possible for rubella IgG specific antibody testing; a frozen aliquot also should be saved for later test ing. If the rubella antibody test result is positive, the mother is likely immune. If the rubella antibody test is negative, a second specimen should be obtained 2 3 weeks later and tested concurrently with the saved specimen. If both of these samples test negative, a third specimen should be obtained 6 weeks after exposure and tested concurrently with the saved specimen. If both the second and third specimens test negative, infection has not occurred. A negative first specimen and a positive test result in either the second or third speci men indicate that seroconversion has occurred in the mother, sug gesting recent infection. Counseling should be provided about the risks and benefits of termination of pregnancy. The routine use of immunoglobulin for susceptible pregnant women exposed to rubella is not recommended and is considered only if termination of preg nancy is not an option because of maternal preferences. In such cir cumstances, immunoglobulin 0.55 mLkg intramuscularly may be given with the understanding that prophylaxis may reduce the risk for clinically apparent infection but does not guarantee prevention of fetal infection. |
7,681 | VACCINATION Rubella vaccine in the United States consists of the attenuated Wis tar RA 273 strain that is usually administered in combination with measles and mumps (MMR) or also with varicella (MMRV) in a two dose regimen at 12 15 months and 4 6 years of age. It theoreti cally may be effective as postexposure prophylaxis if administered within 3 days of exposure. Vaccine should not be administered to severely immunocompromised patients. Patients with HIV infec tion who are not severely immunocompromised may benefit from vaccination. Fever is not a contraindication, but if a more serious illness is suspected, immunization should be delayed. Immuno globulin preparations may inhibit the serologic response to the vaccine (see Chapter 215). Vaccine should not be administered dur ing pregnancy. If pregnancy occurs within 28 days of immuniza tion, the patient should be counseled on the theoretical risks to the fetus. Studies of more than 200 women who had been inadvertently immunized with rubella vaccine during pregnancy showed that none of their offspring developed CRS. Therefore interruption of pregnancy is probably not warranted. Following a single dose of rubella RA 273 vaccine, 95 of persons 12 months of age and older develop serologic immunity, and after two doses 99 have detectable antibody. Rubella RA 273 vaccine is highly protective, because 97 of those vaccinated are protected from clini cal disease after one dose. Detectable antibodies remain for 15 years in most individuals vaccinated after one dose, and 91100 had anti bodies after 12 15 years after two doses. Although antibody levels may wane, especially after one dose of vaccine, increased susceptibility to rubella disease does not occur. Adverse reactions to rubella vaccination are uncommon in children. MMR administration is associated with fever in 515 of vaccinees and with rash in approximately 5 of vaccinees. Arthralgia and arthritis are more common after rubella vaccina tion in adults. Approximately 25 of postpubertal women expe rience arthralgia, and 10 of postpubertal women experience arthritis. Peripheral neuropathies and transient thrombocytope nia may also occur. As part of the worldwide effort to eliminate endemic rubella virus transmission and occurrence of CRS, maintaining high population immunity through vaccination coverage and high quality integrated measles rubella surveillance have been emphasized as being vital to its success. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for a Bibliography. Fig. 294.4 Bilateral cataracts in infant with congenital rubella syndrome. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 295 u Mumps 1969 Mumps is an acute self limited infection that was once commonplace but is now uncommon in countries with widespread use of vaccination. It is characterized by fever, bilateral or unilateral parotid swelling and tenderness, and the frequent occurrence of meningoencephalitis and orchitis. Although infrequent in countries with extensive vaccination programs, mumps remains endemic in the rest of the world, warrant ing continued vaccine protection. Nonetheless, outbreaks of mumps have |
7,682 | been reported in highly vaccinated populations in the United States, particularly among students. ETIOLOGY Mumps virus is in the family Paramyxoviridae and the genus Rubu lavirus. It is a negative sense single stranded nonsegmented RNA virus encapsulated in a lipoprotein envelope possessing seven struc tural proteins. Surface glycoproteins called HN (hemagglutinin neuraminidase) and F (fusion) mediate absorption of the virus to host cells and penetration of the virus into cells, respectively. Both proteins stimulate production of protective antibodies. Mumps virus exists as a single serotype with up to 12 known genotypes, and humans are the only natural host. EPIDEMIOLOGY In the prevaccine era, mumps occurred primarily in young children between the ages of 5 and 9 years and in epidemics about every 4 years. Mumps infection occurred more often in the winter and spring months. In 1968, just after the introduction of the mumps vaccine, 185,691 cases were reported in the United States. Following the recom mendation for routine use of mumps vaccine in 1977, the incidence of mumps fell dramatically in young children (Fig. 295.1) and shifted instead to older children, adolescents, and young adults. Outbreaks continued to occur even in highly vaccinated populations as a result of primary vaccine failure with one dose of vaccine and because of undervaccination of susceptible persons. After implementation of the two dose recommendation for the measles mumps rubella (MMR) vaccine for measles control in 1989, the number of mumps cases declined further. During 20012003, fewer than 300 mumps cases were reported each year. In 2006 the largest mumps epidemic in the past 20 years occurred in the United States. A total of 6,584 cases occurred, 85 of them in 8 midwestern states. Twenty nine percent of the cases occurred in patients 18 24 years old, most of whom were attending college. An analysis of 4,039 patients with mumps seen in the first 7 months of the epidemic indicated that 63 had received more than two doses of the MMR vaccine. Subsequently, several outbreaks of mumps have been documented in highly vaccinated populations in the United States, several in school settings including universities and in Guam. This phenomenon is reported globally as well. The majority of cases in vaccinated persons represent close contact thought to provide intense exposure that may overcome vaccine immunity and perhaps genotype mismatch between circulating mumps genotypes and those in the vac cine. Through 2020, mumps outbreaks have continued to occur, with a peak in 2016 with 6,366 cases, which dropped to 154 in 2021. Mumps is spread from person to person by respiratory droplets. Virus appears in the saliva from up to 7 days before to as long as 7 days after onset of parotid swelling. The period of maximum infectiousness is 1 2 days before to 5 days after onset of parotid swelling. Viral shed ding before onset of symptoms and in asymptomatic infected individu als impairs efforts to contain the infection in susceptible populations. The risk of spreading the virus increases the longer and the closer |
7,683 | the contact a person has with someone who has mumps. The U.S. Centers for Disease Control and Prevention, the American Academy of Pediat rics, and the Health Infection Control Practices Advisory Committee recommend an isolation period of 5 days after onset of parotitis for patients with mumps in both community and healthcare settings. PATHOLOGY AND PATHOGENESIS Mumps virus targets the salivary glands, central nervous system (CNS), pancreas, testes, and, to a lesser extent, thyroid, ovaries, heart, kidneys, liver, and joint synovia. After infection, initial viral replication occurs in the epithelium of the upper respiratory tract. Infection spreads to the adjacent lymph nodes by the lymphatic drainage, and viremia ensues, spreading the virus to targeted tissues, including the meninges, salivary glands, pan creas, testes, and ovaries. Mumps virus causes necrosis of infected cells and is associated with a lymphocytic inflammatory infiltrate. Salivary gland ducts are lined with necrotic epithelium, and the interstitium is infiltrated with lymphocytes. Swelling of tissue within the testes may result in focal ischemic infarcts. The cerebrospinal fluid (CSF) fre quently contains a mononuclear pleocytosis, even in individuals with out clinical signs of meningitis. CLINICAL MANIFESTATIONS The incubation period for mumps ranges from 12 25 days but is usually 16 18 days. Mumps virus infection may result in clinical presentation Chapter 295 Mumps Hayley A. Gans 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0 14 Number of mumps casesUnited States, 19682011 12 10 8 6 4 1 0 1985 1968 1978 1988 1998 2008 1990 2000 20051995 2010 Year Year N o. c as es N o. c as es (in th ou sa nd s) Mumps cases in U.S., by year 7,000 6,000 5,000 4,000 3,000 2,000 1,000 0 20 00 20 01 20 02 20 03 20 04 20 05 20 06 20 07 20 08 20 09 20 10 20 11 20 12 20 13 20 14 20 15 20 16 20 17 A B Fig. 295.1 A, Mumps cases in the United States from 1968, right after the live mumps vaccine was introduced in 1967, to 2011. There was a steady decline following introduction of the vaccine and recommendation for routine vaccination in 1977 (arrow). Note national increases in activity in 19861987, 2006. Mumps data provided were reported voluntarily to the Centers for Disease Control and Prevention (CDC) from state health departments. B, Mumps cases in the United States from 20002017 showing the increased activity in 2006, 2009, 2010, and 20142017. Mumps data provided were reported voluntarily to CDC from state health departments. (A, From McLean HQ, Fiebelkorn AP, Temte JL, et al. Prevention of measles, rubella, congenital rubella syndrome and mumps. MMWR Recomm Rep. 2013;62RR 04:134; B, From Morbidity and Mortality Weekly Report (MMWR): Notifiable Diseases and Mortality Tables. https:www.cdc.govmumpsoutbreaks.html.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1970 Part XV u Infectious Diseases ranging from |
7,684 | asymptomatic (in the prevaccine era 1524 of infec tions were asymptomatic; accurate estimates in the postvaccination era are difficult to measure) or nonspecific symptoms to the typical illness associated with parotitis with or without complications involving sev eral body systems. The typical patient presents with a prodrome lasting 1 2 days consisting of fever, headache, vomiting, malaise, and myalgias. Parotitis follows and may be unilateral initially but becomes bilateral in approximately 70 of cases (Fig. 295.2). The parotid gland is tender, and parotitis may be preceded or accompanied by ear pain on the ipsi lateral side. Ingestion of sour or acidic foods or liquids may enhance pain in the parotid area. As swelling progresses, the angle of the jaw is obscured, and the ear lobe may be lifted upward and outward (see Figs. 295.2 and 295.3). The opening of the Stensen duct may be red and edematous. The parotid swelling peaks in approximately 3 days and then gradually subsides over 7 days. Fever and the other systemic symptoms resolve in 3 5 days. A morbilliform rash is rarely seen. Sub mandibular salivary glands may also be involved or may be enlarged without parotid swelling. Edema over the sternum as a result of lym phatic obstruction may also occur. Symptoms in immunized individu als are the same but tend to be less severe, and parotitis may be absent. DIAGNOSIS When mumps was highly prevalent, the diagnosis could be made on the basis of a history of exposure to mumps infection, an appropriate incubation period, and development of typical clinical findings. Confir mation of the presence of parotitis could be made with demonstration of an elevated serum amylase value. Leukopenia with a relative lympho cytosis was a common finding. Currently, in highly immunized popula tions patients with parotitis lasting longer than 2 days and of unknown cause, a specific diagnosis of mumps should be confirmed or ruled out by virologic or serologic examination. This step may be accomplished by isolation of the virus in cell culture, detection of viral antigen by direct immunofluorescence, or identification of nucleic acid by reverse tran scriptase polymerase chain reaction (PCR). Virus can be isolated from upper respiratory tract secretions (buccal and oropharyngeal mucosa), CSF, or urine during the acute illness; however, PCR from the oropha ryngeal secretions becomes negative quickly, especially in immunized individuals, and thus should be run within 3 days of parotid swelling. Serologic testing is usually a more convenient and available mode of diagnosis. A significant increase in serum mumps immunoglobulin G (IgG) antibody between acute and convalescent serum specimens as detected by complement fixation, neutralization hemagglutination, or enzyme immunoassay tests establishes the diagnosis. Mumps IgG anti bodies may cross react with antibodies to parainfluenza virus in sero logic testing. More commonly, an enzyme immunoassay for mumps IgM antibody is used to identify recent infection. All serologic tests are difficult to interpret in immunized individuals, and negative test results do not rule out mumps infection. Skin testing for mumps is neither sensitive nor |
7,685 | specific and should not be used. DIFFERENTIAL DIAGNOSIS Parotid swelling may be caused by many other infectious and noninfec tious conditions, especially in sporadic cases. Viruses that cause par otitis include parainfluenza 1 and parainfluenza 3 viruses, influenza A virus, cytomegalovirus, Epstein Barr virus, enteroviruses, lymphocytic choriomeningitis virus, and HIV. Purulent parotitis, usually caused by Staphylococcus aureus, is unilateral, is extremely tender, is associated with an elevated white blood cell count, and may involve purulent drain age from the Stensen duct. Submandibular or anterior cervical adenitis from a variety of pathogens may also be confused with parotitis. Other noninfectious causes of parotid swelling include obstruction of the Stensen duct, collagen vascular diseases such as Sjgren syndrome, sys temic lupus erythematosus, immunologic diseases, tumor, and drugs. COMPLICATIONS The most common complications of mumps are meningitis, with or without encephalitis, and gonadal (orchitis, oophoritis) involvement. Uncommon complications include conjunctivitis, optic neuritis, pneumonia, nephritis, pancreatitis, mastitis, and thrombocytopenia. Complications can occur in the absence of parotitis, especially in immunized individuals, and overall complication rates in immunized individuals are lower than in unimmunized and are shifted toward the adult populations. Maternal infection with mumps during the first trimester of preg nancy results in increased fetal wastage. No fetal malformations have been associated with intrauterine mumps infection. However, perina tal mumps disease has been reported in infants born to mothers who acquired mumps late in gestation. Meningitis and Meningoencephalitis Mumps virus is neurotropic and is thought to enter the CNS via the choroid plexus and infect the choroidal epithelium and ependymal cells, both of which can be found in CSF along with mononuclear leukocytes. In the prevaccine era mumps represented one of the most common causes of aseptic meningitis and hearing loss among chil dren. Symptomatic CNS involvement occurs in 1030 of infected individuals, but CSF pleocytosis has been found in 4060 of patients with mumps parotitis. The meningoencephalitis may occur before, along with, or following the parotitis. It most commonly manifests 5 days after the parotitis. Clinical findings vary with age. Infants and young children have fever, malaise, and lethargy, whereas older chil dren, adolescents, and adults complain of headache and demonstrate Eargland axis Parotid gland Sternocleidomastoid muscle Fig. 295.2 Schematic of a parotid gland infected with mumps (right) compared with a normal gland (left). An imaginary line bisecting the long axis of the ear divides the parotid gland into two equal parts. These anatomic relationships are not altered in the enlarged gland. An enlarged cervical lymph node is usually posterior to the imaginary line. (From Mumps epidemic parotitis. In Krugman S, Ward R, Katz SL, eds. Infectious Diseases in Children, 6th ed. St. Louis: Mosby; 1977:182.) Fig. 295.3 A child with mumps showing parotid swelling. (From the Centers for Disease Control and Prevention. Public Health Image Li brary PHIL, Image 4491. https:phil.cdc.govDetails.aspx?pid4491.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. |
7,686 | All rights reserved. Chapter 295 u Mumps 1971 meningeal signs. In a series of children with mumps and meningeal involvement, findings were fever in 94, vomiting in 84, headache in 47, parotitis in 47, neck stiffness in 71, lethargy in 69, and seizures in 18. In typical cases, symptoms resolve in 7 10 days. CSF in mumps meningitis has a white blood cell pleocytosis of 200 600 L with a predominance of lymphocytes. The CSF glucose content is normal in most patients, but a moderate hypoglycorrhachia (glucose content 20 40 mgdL) may be seen in 1020 of patients. The CSF protein content is normal or mildly elevated. Less common CNS complications of mumps include transverse myelitis, acute disseminated encephalomyelitis (ADEM), aqueductal stenosis, and facial palsy. Sensorineural hearing loss is rare and has been estimated to occur in 0.5 5.0 in 100,000 cases of mumps. The hearing loss can be transient. There is some evidence that hearing loss is more likely in patients with meningoencephalitis. Orchitis and Oophoritis In adolescent and adult males, orchitis is second only to parotitis as a common finding in mumps. Involvement in prepubescent boys is extremely rare, but after puberty, orchitis occurs in 3040 of males. It begins within days following onset of parotitis in most cases and is asso ciated with moderate to high fever, chills, and exquisite pain and swelling of the testes. In 30 or less of cases, the orchitis is bilateral. Atrophy of the testes may occur, but sterility is rare even with bilateral involvement. Oophoritis is uncommon in postpubertal females but may cause severe pain and may be confused with appendicitis when located on the right side. Pancreatitis Pancreatitis may occur in mumps with or without parotid involve ment. Severe disease is rare, but fever, epigastric pain, and vomiting are suggestive. Epidemiologic studies have suggested that mumps may be associated with the subsequent development of diabetes mellitus, but a causal link has not been established. Cardiac Involvement Myocarditis has been reported in mumps, and molecular studies have identified mumps virus in heart tissue taken from patients with endo cardial fibroelastosis. Arthritis Arthralgia, monoarthritis, and migratory polyarthritis have been reported in mumps. Arthritis is seen with or without parotitis and usu ally occurs within 3 weeks of onset of parotid swelling. It is generally mild and self limited. Thyroiditis Thyroiditis is rare following mumps. It has not been reported with out parotitis and may occur weeks after the acute infection. Most cases resolve, but some become relapsing and result in hypothyroidism. TREATMENT No specific antiviral therapy is available for mumps. Management should be aimed at reducing the pain associated with meningitis or orchitis and maintaining adequate hydration. Antipyretics may be given for fever. PROGNOSIS The outcome of mumps is nearly always excellent, even when the dis ease is complicated by encephalitis, although fatal cases from CNS involvement or myocarditis have been reported. No mumps deaths have occurred in the recent outbreaks in the United States. PREVENTION Immunization with the live mumps vaccine |
7,687 | is the primary mode of prevention used in the United States. It is given as part of the MMR two dose vaccine schedule, at 12 15 months of age for the first dose and 4 6 years of age for the second dose. If not given at 4 6 years, the second dose should be given before children enter puberty. In those traveling, two doses are recommended in individuals older than 12 months administered at least 28 days apart. Antibody develops in 94 (range: 8997) after one dose. Antibody levels achieved after vaccina tion are lower than after natural infection. The median vaccine effectiveness of mumps vaccine after one dose of vaccine is 78 (range: 4992) and after two doses is 88 (range: 6695). Duration of effectiveness is 10 years after one dose and 15 years after two doses. During outbreaks, a third MMR dose administered to the at risk population was associated with improved outbreak control with sig nificantly fewer cases in those receiving the third dose compared with those not receiving it. Despite these results, modeling supports the cur rent two dose schedule without a routine third booster dose because the current regimen significantly controls size of outbreaks, severity of disease, and number of hospitalizations, whereas the third dose appears to be a possible strategy during an outbreak. As a live virus vaccine, MMR should not be administered to preg nant women or to severely immunodeficient or immunosuppressed individuals. HIV infected patients who are not severely immunocom promised may receive the vaccine, because the risk for severe infec tion with mumps outweighs the risk for serious reaction to the vaccine. Individuals with anaphylactoid reactions to egg or neomycin may be at risk for immediate type hypersensitivity reactions to the vaccine. Persons with other types of reactions to egg or reactions to other com ponents of the vaccine are not restricted from receiving the vaccine. In 2006, in response to the multistate outbreak in the United States, evidence of immunity to mumps through vaccination was redefined. Acceptable presumptive evidence of immunity to mumps now consists of one of the following: (1) documentation of adequate vaccination at age 12 months or older, (2) laboratory evidence of immunity, (3) birth before 1957, and (4) documentation of physician diagnosed mumps. Evidence of immunity through documentation of adequate vaccina tion is defined as one dose of a live mumps virus vaccine for preschool age children and adults not at high risk and two doses for school age children (i.e., grades K 12) and for adults at high risk (e.g., healthcare workers, international travelers, and students at posthigh school edu cational institutions). All persons who work in healthcare facilities should be immune to mumps. Adequate mumps vaccination for healthcare workers born dur ing or after 1957 consists of two doses of a live mumps virus vaccine. Healthcare workers with no history of mumps vaccination and no other evidence of immunity should receive two doses, with 28 days between doses. Healthcare workers who have received |
7,688 | only one dose previously should receive a second dose. Because birth before 1957 is only pre sumptive evidence of immunity, healthcare facilities should consider recommending one dose of a live mumps virus vaccine for unvacci nated workers born before 1957 who do not have a history of physician diagnosed mumps or laboratory evidence of mumps immunity. During an outbreak, healthcare facilities should strongly consider recommend ing two doses of a live mumps virus vaccine to unvaccinated workers born before 1957 who do not have evidence of mumps immunity. Adverse reactions to mumps virus vaccine are rare. Parotitis and orchitis have been reported rarely. There is inadequate information to make a causal relationship to other reactions, such as febrile seizures, deafness, rash, purpura, encephalitis, and meningitis with the strain of mumps vaccine virus used for immunization in the United States. Higher rates of aseptic meningitis following vaccination for mumps are associated with vaccine strains used elsewhere in the world, includ ing the Leningrad 3 and Urabe Am 9 strains. Transient suppression of reactivity to tuberculin skin testing has been reported after mumps vaccination. In 2005 the quadrivalent measles, mumps, rubella, and varicella (MMRV) vaccine was made available. However, in 2010, studies showed a greater risk of febrile seizures in children 12 23 months of age 5 12 days after administration of the vaccine. No increased risk of seizures was seen in children receiving the first dose of the MMRV at older than 48 months of age. As a result, the American Academy of Pediatrics currently recommends either the MMR vaccine and separate varicella vaccine or the MMRV vaccine in children 12 47 months of age. After 48 months of age, the MMRV is generally preferred. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1972 Part XV u Infectious Diseases ETIOLOGY The polioviruses are nonenveloped, positive stranded RNA viruses belonging to the Picornaviridae family, in the genus Enterovirus, spe cies enterovirus C and consist of three antigenically distinct serotypes (types 1, 2, and 3). Polioviruses spread from the intestinal tract to the central nervous system (CNS), where they cause aseptic meningitis and poliomyelitis, or polio. The polioviruses are extremely hardy and can retain infectivity for several days at room temperature. EPIDEMIOLOGY The most devastating result of poliovirus infection is paralysis, although 9095 of infections are inapparent. Despite the absence of symptoms, clinically inapparent infections induce protective immunity. Clinically apparent but nonparalytic illness occurs in approximately 5 of all infections, with paralytic polio occurring in approximately 1 in 1,000 infections among infants to approximately 1 in 100 infections among adolescents. In industrialized countries before universal vaccination, epidemics of paralytic poliomyelitis occurred primarily in adolescents. Conversely, in developing coun tries with poor sanitation, infection early in life results in infantile paralysis. Improved sanitation explains the virtual eradication of polio from the |
7,689 | United States in the early 1960s, when only approxi mately 65 of the population was immunized with the Salk vaccine, which contributed to the disappearance of circulating wild type poliovirus in the United States and Europe. TRANSMISSION Humans are the only known reservoir for the polioviruses, which are spread by the fecal oral route. Poliovirus has been isolated from feces for longer than 2 weeks before paralysis to several weeks after the onset of symptoms. PATHOGENESIS Polioviruses infect cells by adsorbing to the genetically determined poliovirus receptor (CD155). The virus penetrates the cell, is uncoated, and releases viral RNA. The RNA is translated to produce proteins responsible for replication of the RNA, shutoff of host cell protein synthesis, and synthesis of structural elements that compose the capsid. Mature virus particles are produced in 6 8 hours and are released into the environment by disruption of the cell. In the contact host, wild type and vaccine strains of polioviruses gain host entry via the gastrointestinal tract. Recent studies in non human primates demonstrate that the primary sites of replication are in the CD155 epithelial cells lining the mucosa of the tonsil follicle and small intestine, as well as in the macrophagesdendritic cells in the tonsil follicle and Peyer patches. Regional lymph nodes are infected, and primary viremia occurs after 2 3 days. The virus seeds multiple sites, including the reticuloendothelial system, brown fat deposits, and skeletal muscle. Wild type poliovirus probably accesses the CNS along peripheral nerves. Vaccine strains of polioviruses do not replicate in the CNS, a feature that accounts for the safety of the live attenuated vaccine. Occasional revertants (by nucleotide substitution) of these vaccine strains develop a neurovirulent phenotype and cause vaccine associated paralytic poliomyelitis (VAPP). Reversion occurs in the small intestine and probably accesses the CNS via the peripheral nerves. Poliovirus has almost never been cultured from the cerebro spinal fluid (CSF) of patients with paralytic disease, and patients with aseptic meningitis caused by poliovirus never have paralytic disease. With the first appearance of non CNS symptoms, a secondary viremia probably occurs as a result of enormous viral replication in the reticu loendothelial system. The exact mechanism of entry into the CNS is not known. How ever, once entry is gained, the virus may traverse neural pathways, and multiple sites within the CNS are often affected. The effect on motor and autonomic neurons is most striking and correlates with the clini cal manifestations. Perineuronal inflammation, a mixed inflammatory reaction with both polymorphonuclear leukocytes and lymphocytes, is associated with extensive neuronal destruction. Petechial hemorrhages and considerable inflammatory edema also occur in areas of poliovi rus infection. The poliovirus primarily infects motor neuron cells in the spinal cord (the anterior horn cells) and the medulla oblongata (the cranial nerve nuclei). Because of the overlap in muscle innerva tion by two to three adjacent segments of the spinal cord, clinical signs of weakness in the limbs develop when more than 50 of motor neu rons are destroyed. In the medulla, |
7,690 | less extensive lesions cause paraly sis, and involvement of the reticular formation that contains the vital centers controlling respiration and circulation may have a catastrophic outcome. Involvement of the intermediate and dorsal areas of the horn and the dorsal root ganglia in the spinal cord results in hyperesthe sia and myalgias that are typical of acute poliomyelitis. Other neurons affected are the nuclei in the roof and vermis of the cerebellum, the substantia nigra, and, occasionally, the red nucleus in the pons; there may be variable involvement of thalamic, hypothalamic, and pallidal nuclei and the motor cortex. Apart from the histopathology of the CNS, inflammatory changes occur generally in the reticuloendothelial system. Inflammatory edema and sparse lymphocytic infiltration are prominently associated with hyperplastic lymphocytic follicles. Infants acquire immunity transplacentally from their mothers. Transplacental immunity disappears at a variable rate during the first 4 6 months of life. Active immunity after natural infection is probably lifelong but protects against the infecting serotype only; infections with other serotypes are possible. Poliovirus neutralizing antibodies develop within several days after exposure as a result of replication of the virus in the tonsils and in the intestinal tract and deep lymphatic tissues. This early production of circulating immunoglobulin (Ig) G antibodies protects against CNS invasion. Local (mucosal) immunity, conferred mainly by secretory IgA, is an important defense against subsequent reinfection of the gastrointestinal tract. CLINICAL MANIFESTATIONS The incubation period of poliovirus from contact to initial clinical symptoms is usually considered to be 8 12 days, with a range of 5 35 days. Poliovirus infections with wild type virus may follow one of sev eral courses: inapparent infection, which occurs in 9095 of cases and causes no disease and no sequelae; abortive poliomyelitis; non paralytic poliomyelitis; or paralytic poliomyelitis. Paralysis, if it occurs, appears 3 8 days after the initial symptoms. The clinical manifestations of paralytic polio caused by wild or vaccine strains are comparable, although the incidence of abortive and nonparalytic paralysis with vaccine associated poliomyelitis is unknown. Abortive Poliomyelitis In approximately 5 of patients, a nonspecific influenza like syndrome occurs 1 2 weeks after infection, which is termed abortive poliomyeli tis. Fever, malaise, anorexia, and headache are prominent features, and there may be sore throat and abdominal or muscular pain. Vomiting occurs irregularly. The illness is short lived, lasting up to 2 3 days. The physical examination may be normal or may reveal nonspecific phar yngitis, abdominal or muscular tenderness, and weakness. Recovery is complete, and no neurologic signs or sequelae develop. Nonparalytic Poliomyelitis In approximately 1 of patients infected with wild type poliovirus, signs of abortive poliomyelitis are present, as are more intense head ache, nausea, and vomiting, as well as soreness and stiffness of the posterior muscles of the neck, trunk, and limbs. Fleeting paralysis of the bladder and constipation are frequent. Approximately two thirds Chapter 296 Polioviruses Eric A.F. Simes Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use |
7,691 | only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 296 u Polioviruses 1973 of these children have a short symptom free interlude between the first phase (minor illness) and the second phase (CNS disease or major ill ness). Nuchal rigidity and spinal rigidity are the basis for the diagnosis of nonparalytic poliomyelitis during the second phase. Physical examination reveals nuchal spinal signs and changes in superficial and deep reflexes. Gentle forward flexion of the occiput and neck elicits nuchal rigidity. The examiner can demonstrate head drop by placing the hands under the patients shoulders and raising the patients trunk. Although normally the head follows the plane of the trunk, in poliomyelitis it often falls backward limply, but this response is not attributable to true paresis of the neck flexors. In struggling infants, it may be difficult to distinguish voluntary resistance from clinically important true nuchal rigidity. The examiner may place the infants shoulders flush with the edge of the table, support the weight of the occiput in the hand, and then flex the head anteriorly. True nuchal rigidity persists during this maneuver. When open, the anterior fonta nel may be tense or bulging. In the early stages the reflexes are normally active and remain so unless paralysis supervenes. Changes in reflexes, either increased or decreased, may precede weakness by 12 24 hours. The superficial reflexes, the cremasteric and abdominal reflexes, and the reflexes of the spinal and gluteal muscles are usually the first to diminish. The spinal and gluteal reflexes may disappear before the abdominal and cremas teric reflexes. Changes in the deep tendon reflexes generally occur 8 24 hours after the superficial reflexes are depressed and indicate impend ing paresis of the extremities. Tendon reflexes are absent with paralysis. Sensory defects do not occur in poliomyelitis. Paralytic Poliomyelitis Paralytic poliomyelitis develops in approximately 0.1 of persons infected with poliovirus, causing 3 clinically recognizable syndromes that represent a continuum of infection differentiated only by the por tions of the CNS most severely affected. These are (1) spinal paralytic poliomyelitis, (2) bulbar poliomyelitis, and (3) polioencephalitis. Spinal paralytic poliomyelitis may occur as the second phase of a biphasic illness, the first phase of which corresponds to abortive polio myelitis. The patient then appears to recover and feels better for 2 5 days, after which severe headache and fever occur with exacerbation of the previous systemic symptoms. Severe muscle pain is present, and sensory and motor phenomena (e.g., paresthesia, hyperesthesia, fas ciculations, and spasms) may develop. On physical examination the distribution of paralysis is characteristically spotty. Single muscles, multiple muscles, or groups of muscles may be involved in any pat tern. Within 1 2 days, asymmetric flaccid paralysis or paresis occurs. Involvement of one leg is most common, followed by involvement of one arm. The proximal areas of the extremities tend to be involved to a greater extent than the distal areas. To detect mild muscular weak ness, it is often necessary to apply gentle resistance in |
7,692 | opposition to the muscle group being tested. Examination at this point may reveal nuchal stiffness or rigidity, muscle tenderness, initially hyperactive deep tendon reflexes (for a short period) followed by absence or dimi nution of reflexes, and paresis or flaccid paralysis. In the spinal form, there is weakness of some of the muscles of the neck, abdomen, trunk, diaphragm, thorax, or extremities. Sensation is intact; sensory distur bances, if present, suggest a disease other than poliomyelitis. The paralytic phase of poliomyelitis is extremely variable; some patients progress during observation from paresis to paralysis, whereas others recover, either slowly or rapidly. The extent of paresis or paraly sis is directly related to the extent of neuronal involvement; paralysis occurs if 50 of the neurons supplying the muscles are destroyed. The extent of involvement is usually obvious within 2 3 days; only rarely does progression occur beyond this interval. Bowel and blad der dysfunction ranging from transient incontinence to paralysis with constipation and urinary retention often accompany paralysis of the lower limbs. The onset and course of paralysis are variable in developing coun tries. The biphasic course is rare; typically the disease manifests in a single phase in which prodromal symptoms and paralysis occur in a continuous fashion. In developing countries, where a history of intramuscular injections precedes paralytic poliomyelitis in approxi mately 5060 of patients, patients may present initially with fever and paralysis (provocation paralysis). The degree and duration of muscle pain are also variable, ranging from a few days usually to a week. Occa sionally, spasm and increased muscle tone with a transient increase in deep tendon reflexes occur in some patients, whereas in most patients, flaccid paralysis occurs abruptly. Once the temperature returns to nor mal, progression of paralytic manifestations stops. Little recovery from paralysis is noted in the first days or weeks, but, if it is to occur, it is usu ally evident within 6 months. The return of strength and reflexes is slow and may continue to improve for as long as 18 months after the acute disease. Lack of improvement from paralysis within the first several weeks or months after onset is usually evidence of permanent paralysis. Atrophy of the limb, failure of growth, and deformity are common and are especially evident in the growing child. Bulbar poliomyelitis may occur as a clinical entity without appar ent involvement of the spinal cord. Infection is a continuum, and designation of the disease as bulbar implies only dominance of the clinical manifestations by dysfunctions of the cranial nerves and medullary centers. The clinical findings seen with bulbar poliomy elitis with respiratory difficulty (other than paralysis of extraocular, facial, and masticatory muscles) include (1) nasal twang to the voice or cry caused by palatal and pharyngeal weakness (hard consonant words such as cookie and candy bring this feature out best); (2) inability to swallow smoothly, resulting in accumulation of saliva in the pharynx, indicating partial immobility (holding the larynx lightly and asking the patient to swallow will confirm such |
7,693 | immobility); (3) accumulated pharyngeal secretions, which may cause irregular res pirations that appear interrupted and abnormal even to the point of falsely simulating intercostal or diaphragmatic weakness; (4) absence of effective coughing, shown by constant fatiguing efforts to clear the throat; (5) nasal regurgitation of saliva and fluids as a result of palatal paralysis, with inability to separate the oropharynx from the nasopharynx during swallowing; (6) deviation of the palate, uvula, or tongue; (7) involvement of vital centers in the medulla, which mani fest as irregularities in rate, depth, and rhythm of respiration and as cardiovascular alterations, including blood pressure changes (espe cially increased blood pressure), alternate flushing and mottling of the skin, and cardiac arrhythmias; and as rapid changes in body tem perature; (8) paralysis of one or both vocal cords, causing hoarseness, aphonia, and, ultimately, asphyxia unless the problem is recognized on laryngoscopy and managed by immediate tracheostomy; and (9) the rope sign, an acute angulation between the chin and larynx caused by weakness of the hyoid muscles (the hyoid bone is pulled posteriorly, narrowing the hypopharyngeal inlet). Uncommonly, bulbar disease may culminate in an ascending paraly sis (Landry type), in which there is progression cephalad from initial involvement of the lower extremities. Hypertension and other auto nomic disturbances are common in bulbar involvement and may per sist for a week or more or may be transient. Occasionally, hypertension is followed by hypotension and shock and is associated with irregular or failed respiratory effort, delirium, or coma. This kind of bulbar dis ease may be rapidly fatal. The course of bulbar disease is variable; some patients die as a result of extensive, severe involvement of the various centers in the medulla; others recover partially but require ongoing respiratory support, and others recover completely. Cranial nerve involvement is seldom per manent. Atrophy of muscles may be evident, patients immobilized for long periods may experience pneumonia, and renal stones may form as a result of hypercalcemia and hypercalciuria secondary to bone resorption. Polioencephalitis is a rare form of the disease in which higher centers of the brain are severely involved. Seizures, coma, and spas tic paralysis with increased reflexes may be observed. Irritability, dis orientation, drowsiness, and coarse tremors are often present with peripheral or cranial nerve paralysis that coexists or ensues. Hypoxia and hypercapnia caused by inadequate ventilation due to respiratory insufficiency may produce disorientation without true encephalitis. The manifestations are common to encephalitis of any cause and can be Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1974 Part XV u Infectious Diseases attributed to polioviruses only with specific viral diagnosis or if accom panied by flaccid paralysis. Paralytic poliomyelitis with ventilatory insufficiency results from several components acting together to produce ventilatory insuf ficiency resulting in hypoxia and hypercapnia. It may have profound effects on many other systems. Because respiratory insufficiency may |
7,694 | develop rapidly, close continued clinical evaluation is essential. Despite weakness of the respiratory muscles, the patient may respond with so much respiratory effort associated with anxiety and fear that overven tilation may occur at the outset, resulting in respiratory alkalosis. Such effort is fatiguing and contributes to respiratory failure. There are certain characteristic patterns of disease. Pure spinal polio myelitis with respiratory insufficiency involves tightness, weakness, or paralysis of the respiratory muscles (chiefly the diaphragm and inter costals) without discernible clinical involvement of the cranial nerves or vital centers that control respiration, circulation, and body tempera ture. The cervical and thoracic spinal cord segments are chiefly affected. Pure bulbar poliomyelitis involves paralysis of the motor cranial nerve nuclei with or without involvement of the vital centers. Involvement of the 9th, 10th, and 12th cranial nerves results in paralysis of the phar ynx, tongue, and larynx with consequent airway obstruction. Bulbos pinal poliomyelitis with respiratory insufficiency affects the respiratory muscles and results in coexisting bulbar paralysis. The clinical findings associated with involvement of the respiratory muscles include (1) anxious expression; (2) inability to speak with out frequent pauses, resulting in short, jerky, breathless sentences; (3) increased respiratory rate; (4) movement of the alae nasi and of the accessory muscles of respiration; (5) inability to cough or sniff with full depth; (6) paradoxical abdominal movements caused by diaphragmatic immobility caused by spasm or weakness of one or both leaves; and (7) relative immobility of the intercostal spaces, which may be segmental, unilateral, or bilateral. When the arms are weak, and especially when deltoid paralysis occurs, there may be impending respiratory paraly sis because the phrenic nerve nuclei are in adjacent areas of the spinal cord. Observation of the patients capacity for thoracic breathing while the abdominal muscles are splinted manually indicates minor degrees of paresis. Light manual splinting of the thoracic cage helps to assess the effectiveness of diaphragmatic movement. DIAGNOSIS Poliomyelitis should be considered in any unimmunized or incom pletely immunized child with paralytic disease. Although this guideline is most applicable in poliomyelitis endemic countries (Afghanistan, and Pakistan in 2023), the spread of polio in 2013 from endemic coun tries to many nonendemic countries (Niger, Chad, Cameroon, Ethio pia, Kenya, Somalia, and Syria) and the isolation of wild poliovirus type 1 in Israel in 2014 and circulating type 1 vaccine associated paralytic polio in Ukraine in 2015 suggest that the diagnosis of polio should be entertained in all countries. VAPP should be considered in any child with paralytic disease occurring 7 14 days after receiving the orally administered polio vaccine (OPV). VAPP can occur at later times after administration and should be considered in any child with paralytic disease in countries or regions where wild type poliovirus has been eradicated and the OPV has been administered to the child or a con tact. The combination of fever, headache, neck and back pain, asym metric flaccid paralysis without sensory loss, and pleocytosis does not regularly occur in any other illness. The World |
7,695 | Health Organization (WHO) recommends that the laboratory diagnosis of poliomyelitis be confirmed by isolation and identification of poliovirus in the stool, with specific identification of wild type and vaccine type strains. In suspected cases of acute flaccid paralysis, two stool specimens should be collected 24 48 hours apart as soon as possible after the diagnosis of poliomyelitis is suspected. Polio virus concentrations are high in the stool in the first week after the onset of paralysis, which is the optimal time for collection of stool spec imens. Polioviruses may be isolated from 8090 of specimens from acutely ill patients, whereas 20 of specimens from such patients may yield virus at 3 4 weeks after onset of paralysis. Because most chil dren with spinal or bulbospinal poliomyelitis have constipation, rectal straws may be used to obtain specimens; ideally a minimum of 8 10 g of stool should be collected. In laboratories that can isolate poliovirus, isolates should be sent to either the U.S. Centers for Disease Control and Prevention (CDC) or to one of the WHO certified poliomyelitis laboratories where DNA sequence analysis can be performed to dis tinguish between wild poliovirus and neurovirulent, revertant OPV strains. With the current WHO plan for global eradication of poliomy elitis, most regions of the world (the Americas, Europe, and Australia) have been certified wild poliovirus free; in these areas, poliomyelitis is most often caused by vaccine strains. Hence it is critical to differentiate between wild type and revertant vaccine type strains. The CSF is often normal during the minor illness and typically con tains a pleocytosis with 20 300 cellsL with CNS involvement. The cells in the CSF may be polymorphonuclear early during the course of the disease but shift to mononuclear cells soon afterward. By the second week of major illness, the CSF cell count falls to near normal values. In contrast, the CSF protein content is normal or only slightly elevated at the outset of CNS disease but usually rises to 50 100 mg dL by the second week of illness. In polioencephalitis, the CSF may remain normal or show minor changes. Serologic testing demonstrates seroconversion or a fourfold or greater increase in antibody titers from the acute phase of illness to 3 6 weeks later. DIFFERENTIAL DIAGNOSIS Poliomyelitis should be considered in the differential diagnosis of any case of paralysis and is only one of many causes of acute flaccid paraly sis (AFP) in children and adults. There are numerous other causes of acute flaccid paralysis (Table 296.1). As evidence of this point, in 2022 of the 57,983 cases of AFP reported to WHO, there were 30 cases of WPV1, 173 of cVDPV1, and 648 cases of cVDPV2. In most conditions, the clinical features are sufficient to differentiate between these various causes, but in some cases nerve conduction studies and electromyo grams, in addition to muscle biopsies, may be required. The possibility of polio should be considered in any case of acute flaccid paralysis, even in countries where polio has |
7,696 | been eradicated. The diagnoses most often confused with polio are VAPP, West Nile virus infection, and infections caused by other enteroviruses (including EV A71 and EV D68), as well as Guillain Barr syndrome, transverse myelitis, and traumatic paralysis. In Guillain Barr syndrome, which is the most difficult to distinguish from poliomyelitis, the paralysis is characteristically symmetric, and sensory changes and pyramidal tract signs are common, contrasting with poliomyelitis. Fever, headache, and meningeal signs are less notable, and the CSF has few cells but an elevated protein content. Transverse myelitis progresses rapidly over hours to days, causing an acute symmetric paralysis of the lower limbs with concomitant anesthesia and diminished sensory perception. Autonomic signs of hypothermia in the affected limbs are common, and there is bladder dysfunction. The CSF is usually normal. Trau matic neuritis occurs from a few hours to a few days after the trau matic event, is asymmetric, is acute, and affects only one limb. Muscle tone and deep tendon reflexes are reduced or absent in the affected limb with pain in the gluteus. The CSF is normal. Conditions causing pseudoparalysis do not present with nuchal spinal rigidity or pleocytosis. These causes include unrecognized trauma, transient (toxic) synovitis, acute osteomyelitis, acute rheu matic fever, scurvy, and congenital syphilis (pseudoparalysis of Parrot). TREATMENT There is no specific antiviral treatment for poliomyelitis. However, pocapavir (a capsid inhibitor) and V 7404 (an enterovirus 3C prote ase inhibitor) are being developed potentially for use in combination for treatment of poliovirus and other enteroviral infections. The man agement is supportive and aimed at limiting progression of disease, preventing ensuing skeletal deformities, and preparing the child and family for the prolonged treatment required and for permanent dis ability if this seems likely. Patients with the nonparalytic and mildly paralytic forms of poliomyelitis may be treated at home. All intramus cular injections and surgical procedures are contraindicated during the Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. C hap ter 2 9 6 u Po lio viruses 1 9 7 5 Table 296.1 Differential Diagnosis of Acute Flaccid Paralysis SITE, CONDITION, FACTOR, OR AGENT CLINICAL FINDINGS ONSET OF PARALYSIS PROGRESSION OF PARALYSIS SENSORY SIGNS AND SYMPTOMS REDUCTION OR ABSENCE OF DEEP TENDON REFLEXES RESIDUAL PARALYSIS PLEOCYTOSIS ANTERIOR HORN CELLS OF SPINAL CORD Poliomyelitis (wild and vaccine associated paralytic poliomyelitis) Paralysis Incubation period 7 14 days (range: 4 35 days) 24 48 hr to onset of full paralysis; proximal distal, asymmetric No Yes Yes Aseptic meningitis (moderate polymorphonuclear leukocytes at 2 3 days) Nonpolio enteroviruses (including EV A71, EV D68) Hand foot and mouth disease, aseptic meningitis, acute hemorrhagic conjunctivitis, possibly idiopathic epidemic flaccid paralysis As in poliomyelitis As in poliomyelitis No Yes Yes As in poliomyelitis West Nile virus Meningitis encephalitis As in poliomyelitis As in poliomyelitis No Yes Yes Yes OTHER NEUROTROPIC VIRUSES Rabies virus Mo to yr |
7,697 | Acute, symmetric, ascending Yes Yes No Varicella zoster virus Exanthematous vesicular eruptions Incubation period 10 21 days Acute, symmetric, ascending Yes Yes Japanese encephalitis virus Incubation period 5 15 days Acute, proximal, asymmetric Yes GUILLAIN BARR SYNDROME Acute inflammatory polyradiculo neuropathy Preceding infection, bilateral facial weakness Hr to 10 days Acute, symmetric, ascending (days to 4 wk) Yes Yes No Acute motor axonal neuropathy Fulminant, widespread paralysis, bilateral facial weakness, tongue involvement Hr to 10 days 1 6 days No Yes No Continued D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. 1 9 7 6 P art X V u Infectious D iseases Table 296.1 Differential Diagnosis of Acute Flaccid Paralysiscontd SITE, CONDITION, FACTOR, OR AGENT CLINICAL FINDINGS ONSET OF PARALYSIS PROGRESSION OF PARALYSIS SENSORY SIGNS AND SYMPTOMS REDUCTION OR ABSENCE OF DEEP TENDON REFLEXES RESIDUAL PARALYSIS PLEOCYTOSIS ACUTE TRAUMATIC SCIATIC NEURITIS Intramuscular gluteal injection Acute, asymmetric Hr to 4 days Complete, affected limb Yes Yes No Acute transverse myelitis Preceding Mycoplasma pneumoniae, Schistosoma, other parasitic or viral infection Acute, symmetric hypotonia of lower limbs Hr to days Yes Yes, early Yes Yes Epidural abscess Headache, back pain, local spinal tenderness, meningismus Complete Yes Yes Yes Spinal cord compression; trauma Complete Hr to days Yes Yes NEUROPATHIES Exotoxin of Corynebacterium diphtheriae In severe cases, palatal paralysis, blurred vision Incubation period 1 8 wk (paralysis 8 12 wk after onset of illness) Yes Yes Toxin of Clostridium botulinum Abdominal pain, diplopia, loss of accommodation, mydriasis Incubation period 18 36 hr Rapid, descending, symmetric No No Tick bite paralysis Ocular symptoms Latency period 5 10 days Acute, symmetric, ascending No Yes No DISEASES OF THE NEUROMUSCULAR JUNCTION Myasthenia gravis Weakness, fatigability, diplopia, ptosis, dysarthria Multifocal No No No No DISORDERS OF MUSCLE Polymyositis Neoplasm, autoimmune disease Subacute, proximal distal Wk to mo No Yes No Viral myositis Pseudoparalysis Hr to days No No No METABOLIC DISORDERS Hypokalemic periodic paralysis Proximal limb, respiratory muscles Sudden postprandial No Yes No INTENSIVE CARE UNIT WEAKNESS Critical illness polyneuropathy Flaccid limbs and respiratory weakness Acute, following systemic inflammatory response syndromesepsis Hr to days Yes No Modified from Marx A, Glass JD, Sutter RW. Differential diagnosis of acute flaccid paralysis and its role in poliomyelitis surveillance. Epidemiol Rev. 2000;22:298316. D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. Chapter 296 u Polioviruses 1977 acute phase of the illness, especially in the first week of illness, because they might result in progression of disease. Abortive Poliomyelitis Supportive |
7,698 | treatment with analgesics, sedatives, an appetizing diet, and bed rest until the childs temperature is normal for several days is usu ally sufficient. Avoidance of exertion for the ensuing 2 weeks is desir able, and careful neurologic and musculoskeletal examinations should be performed 2 months later to detect any minor involvement. Nonparalytic Poliomyelitis Treatment for the nonparalytic form is similar to that for the abor tive form; in particular, relief is indicated for the discomfort of muscle tightness and spasm of the neck, trunk, and extremities. Analgesics are more effective when they are combined with the application of hot packs for 15 30 minutes every 2 4 hours. Hot tub baths are sometimes useful. A firm bed is desirable and can be improvised at home by plac ing table leaves or a sheet of plywood beneath the mattress. A foot board or splint should be used to keep the feet at a right angle to the legs. Because muscular discomfort and spasm may continue for some weeks, even in the nonparalytic form, hot packs and gentle physical therapy may be necessary. Patients with nonparalytic poliomyelitis should also be carefully examined 2 months after apparent recovery to detect minor residual effects that might cause postural problems in later years. Paralytic Poliomyelitis Most patients with the paralytic form of poliomyelitis require hospital ization with complete physical rest in a calm atmosphere for the first 2 3 weeks. Suitable body alignment is necessary for comfort and to avoid excessive skeletal deformity. A neutral position with the feet at right angles to the legs, the knees slightly flexed, and the hips and spine straight is achieved by use of boards, sandbags, and, occasionally, light splint shells. The position should be changed every 3 6 hours. Active and passive movements are indicated as soon as the pain has disappeared. Moist hot packs may relieve muscle pain and spasm. Opiates and seda tives are permissible only if no impairment of ventilation is present or impending. Constipation is common, and fecal impaction should be prevented. When bladder paralysis occurs, a parasympathetic stimulant such as bethanechol may induce voiding in 15 30 minutes; some patients show no response to this agent, and others respond with nausea, vomit ing, and palpitations. Bladder paresis rarely lasts more than a few days. If bethanechol fails, manual compression of the bladder and the psycho logic effect of running water should be tried. If catheterization must be performed, care must be taken to prevent urinary tract infections. An appealing diet and a relatively high fluid intake should be started at once unless the patient is vomiting. Additional salt should be provided if the environmental temperature is high or if the application of hot packs induces sweating. Anorexia is common initially. Adequate dietary and fluid intake can be maintained by placement of a central venous catheter. An orthopedist and a physiatrist should see patients as early in the course of the illness as possible and should assume responsibility for their care before fixed deformities |
7,699 | develop. The management of pure bulbar poliomyelitis consists of maintain ing the airway and avoiding all risk of inhalation of saliva, food, and vomitus. Gravity drainage of accumulated secretions is favored by using the head low (foot of bed elevated 20 25 degrees) prone posi tion with the face to one side. Patients with weakness of the muscles of respiration or swallowing should be nursed in a lateral or semiprone position. Aspirators with rigid or semirigid tips are preferred for direct oral and pharyngeal aspiration, and soft, flexible catheters may be used for nasopharyngeal aspiration. Fluid and electrolyte equilibrium is best maintained by intravenous infusion because tube or oral feeding in the first few days may incite vomiting. In addition to close observation for respiratory insufficiency, the blood pressure should be measured at least twice daily because hypertension is not uncommon and occasion ally leads to hypertensive encephalopathy. Patients with pure bulbar poliomyelitis may require tracheostomy because of vocal cord paralysis or constriction of the hypopharynx; most patients who recover have little residual impairment, although some exhibit mild dysphagia and occasional vocal fatigue with slurring of speech. Impaired ventilation must be recognized early; mounting anxiety, restlessness, and fatigue are early indications for preemptive interven tion. Tracheostomy is indicated for some patients with pure bulbar poliomyelitis, spinal respiratory muscle paralysis, or bulbospinal paral ysis because such patients are generally unable to cough, sometimes for many months. Mechanical respirators are often needed. COMPLICATIONS Paralytic poliomyelitis may be associated with numerous complica tions. Acute gastric dilation may occur abruptly during the acute or convalescent stage, causing further respiratory embarrassment; imme diate gastric aspiration and external application of ice bags are indi cated. Melena severe enough to require transfusion may result from single or multiple superficial intestinal erosions; perforation is rare. Mild hypertension for days or weeks is common in the acute stage and probably related to lesions of the vasoregulatory centers in the medulla and especially to underventilation. In the later stages, because of immo bilization, hypertension may occur along with hypercalcemia, neph rocalcinosis, and vascular lesions. Dimness of vision, headache, and a lightheaded feeling associated with hypertension should be regarded as premonitory of a frank convulsion. Cardiac irregularities are uncom mon, but electrocardiographic abnormalities suggesting myocarditis occur with some frequency. Acute pulmonary edema occurs occasion ally, particularly in patients with arterial hypertension. Hypercalcemia occurs because of skeletal decalcification that begins soon after immo bilization and results in hypercalciuria, which in turn predisposes the patient to urinary calculi, especially when urinary stasis and infection are present. High fluid intake is the only effective prophylactic measure. PROGNOSIS The outcome of inapparent, abortive poliomyelitis and aseptic menin gitis syndromes is uniformly good, with death being exceedingly rare and with no long term sequelae. The outcome of paralytic disease is determined primarily by degree and severity of CNS involvement. In severe bulbar poliomyelitis, the mortality rate may be as high as 60, whereas in less severe bulbar involvement andor spinal poliomyelitis, the mortality rate varies from |
7,700 | 510, death generally occurring from causes other than the poliovirus infection. Maximum paralysis usually occurs 2 3 days after the onset of the paralytic phase of the illness, with stabilization followed by gradual return of muscle function. The recovery phase usually lasts about 6 months, beyond which persisting paralysis is permanent. In gen eral, paralysis is more likely to develop in male children and female adults. Mortality and the degree of disability are greater after the age of puberty. Pregnancy is associated with an increased risk for para lytic disease. Tonsillectomy and intramuscular injections may enhance the risk for acquisition of bulbar and localized disease, respectively. Increased physical activity, exercise, and fatigue during the early phase of illness have been cited as factors leading to a higher risk for paralytic disease. Finally, it has been clearly demonstrated that type 1 poliovirus has the greatest propensity for natural poliomyelitis and type 3 poliovi rus has a predilection for producing VAPP. Postpolio Syndrome After an interval of 30 40 years, as many as 3040 of persons who survived paralytic poliomyelitis in childhood may experience muscle pain and exacerbation of existing weakness or development of new weakness or paralysis. This entity, referred to as postpolio syndrome, has been reported only in persons who were infected in the era of wild type poliovirus circulation. Risk factors for postpolio syndrome include increasing length of time since acute poliovirus infection, pres ence of permanent residual impairment after recovery from acute ill ness, and female sex. PREVENTION Vaccination is the only effective method of preventing poliomyelitis. Hygienic measures help to limit the spread of the infection among Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1978 Part XV u Infectious Diseases young children, but immunization is necessary to control transmis sion among all age groups. Both the inactivated polio vaccine (IPV), which is currently produced using better methods than those for the original vaccine and is sometimes referred to as enhanced IPV, and the live attenuated OPV have established efficacy in preventing polio virus infection and paralytic poliomyelitis. Both vaccines induce pro duction of antibodies against the three strains of poliovirus. IPV elicits higher serum IgG antibody titers, but the OPV also induces signifi cantly greater mucosal IgA immunity in the oropharynx and gastro intestinal tract, which limits replication of the wild poliovirus at these sites. Transmission of wild poliovirus by fecal spread is limited in OPV recipients. The immunogenicity of IPV is not affected by the presence of maternal antibodies, and IPV has no adverse effects. Live vaccine may undergo reversion to neurovirulence as it multiplies in the human intestinal tract and may cause VAPP in vaccinees or in their contacts. The overall risk for recipients varies from 1 case per 750,000 immu nized infants in the United States to 1 in 143,000 immunized infants in India. The risk for |
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